Histone deacetylase inhibitors and compositions and methods of use thereof

ABSTRACT

Provided are certain histone deacetylase (HDAC) inhibitors of Formula I, or pharmaceutically acceptable salts thereof, compositions thereof, and methods of their use. The condition or disorder mediated by HDAC comprises a neurodegenerative pathology. Accordingly, also provided is a method of treating a neurodegenerative pathology mediated by HDAC in a subject in need of such a treatment, comprising administering to the subject a therapeutically effective amount of at least one compound, or pharmaceutically acceptable salt thereof, described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage Application under 35 U.S.C. §371 of PCT Application No. PCT/US2015/033511, filed Jun. 1, 2015, whichclaims the benefit of priority of U.S. Application No. 62/006,534, filedJun. 2, 2014, which is incorporated by reference herein for allpurposes.

Provided herein are certain histone deacetylase (HDAC) inhibitors,compositions thereof, and methods of their use.

Histone deacetylases (HDACs) are zinc-containing enzymes which catalysethe removal of acetyl groups from the ε-amino termini of lysine residuesclustered near the amino terminus of nucleosomal histones. There are 11known metal-dependent human histone deacetylases, grouped into fourclasses based on the structure of their accessory domains. Class Iincludes HDAC1, HDAC2, HDAC3, and HDAC8 and have homology to yeast RPD3.HDAC4, HDAC5, HDAC7, and HDAC9 belong to Class IIa and have homology toyeast HDAC1. HDAC6 and HDAC10 contain two catalytic sites and areclassified as Class IIb, whereas HDAC11 has conserved residues in itscatalytic center that are shared by both Class I and Class IIdeacetylases and is sometimes placed in Class IV.

Provided is a compound of Formula I, or a pharmaceutically acceptablesalt thereof,

wherein:

-   R¹ is chosen from —C(O)NH(OH) and —N(OH)C(O)R⁹;-   R² is chosen from aryl, heteroaryl, and heterocycloalkyl, each of    which is optionally substituted with 1 to 3 substituents    independently chosen from halo, alkyl, cycloalkyl, haloalkyl,    hydroxyl, alkoxy, and nitrile;-   A is chosen from aryl and heteroaryl;-   R³ and R⁴ are independently chosen from hydrogen, alkyl, halo,    NHSO₂R¹⁰, C(O)NR¹¹R¹², NR¹¹R¹², nitrile, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each    of which is optionally substituted with 1 to 3 substituents    independently chosen from halo, alkyl, cycloalkyl, haloalkyl,    hydroxyl, alkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and    alkoxy are optionally substituted with amino, (alkyl)amino or    di(alkyl)amino;-   for each occurrence, R⁵, R⁶, R⁷, and R⁸ are independently chosen    from hydrogen and lower alkyl;-   R⁹ is chosen from hydrogen and lower alkyl;-   R¹⁶ is chosen from lower alkyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl;-   R¹¹ and R¹² are independently chosen from hydrogen, lower alkyl,    alkoxy, lower haloalkyl and cycloalkyl wherein alkyl and alkoxy are    optionally substituted with amino, (alkyl)amino or di(alkyl)amino,    and-   m and m′ are independently chosen from 0, 1, 2, 3 and 4, provided    that 2≤(m+m′)≤4.

Also provided is a pharmaceutical composition comprising a compound, ora pharmaceutically acceptable salt thereof, described herein and atleast one pharmaceutically acceptable excipient.

Also provided is a method of treating a condition or disorder mediatedby at least one histone deacetylase in a subject in need of such atreatment which method comprises administering to the subject atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, described herein.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having, forexample, the indicated number of carbon atoms, usually from 1 to 20carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbonatoms. For example C₁-C₆ alkyl encompasses both straight and branchedchain alkyl of from 1 to 6 carbon atoms. Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, and the like. Alkylene is another subset ofalkyl, referring to the same residues as alkyl, but having two points ofattachment. Alkylene groups will usually have from 2 to 20 carbon atoms,for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. Forexample, C₀ alkylene indicates a covalent bond and C₁ alkylene is amethylene group. When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed; thus, for example, “butyl” is meant toinclude n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includesn-propyl and isopropyl.

“Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ringhaving, for example, the indicated number of carbon atoms, for example,3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups maybe monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl and cyclohexyl, as well as bridged and caged ring groups(e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of apolycyclic cycloalkyl group may be aromatic, provided the polycycliccycloalkyl group is bound to the parent structure via a non-aromaticcarbon. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (whereinthe moiety is bound to the parent structure via a non-aromatic carbonatom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a cycloalkyl group.

“Cycloalkenyl” indicates a non-aromatic ring having 3 to 10, or 3 to 8,or 3 to 6 ring carbon atoms, and at least one double bond derived by theremoval of one molecule of hydrogen from two adjacent carbon atoms ofthe corresponding cycloalkyl.

By “alkoxy” is meant an alkyl group, for example, of the indicatednumber of carbon atoms attached through an oxygen bridge such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy,2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. Alkoxy groups willusually have from 1 to 6 carbon atoms attached through the oxygenbridge.

“Aryl” indicates an aromatic carbon ring having, for example, theindicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbonatoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic). In some instances, both rings of a polycyclic aryl group arearomatic (e.g., naphthyl). In other instances, polycyclic aryl groupsmay include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring,provided the polycyclic aryl group is bound to the parent structure viaan atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-ylgroup (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered an aryl group, while1,2,3,4-tetrahydronaphthalen-1-yl (wherein the moiety is bound to theparent structure via a non-aromatic carbon atom) is not considered anaryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (whereinthe moiety is bound to the parent structure via an aromatic carbon atom)is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl group(wherein the moiety is bound to the parent structure via a non-aromaticnitrogen atom) is not considered an aryl group. However, the term “aryl”does not encompass or overlap with “heteroaryl”, as defined herein,regardless of the point of attachment (e.g., both quinolin-5-yl andquinolin-2-yl are heteroaryl groups). In some instances, aryl is phenylor naphthyl. In certain instances, aryl is phenyl.

Bivalent radicals formed from substituted benzene derivatives and havingthe free valences at ring atoms are named as substituted phenyleneradicals. Bivalent radicals derived from univalent polycyclichydrocarbon radicals whose names end in “-yl” by removal of one hydrogenatom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., anaphthyl group with two points of attachment is termed naphthylidene.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Heteroaryl” indicates an aromatic ring containing, for example, theindicated number of atoms (e.g., 5 to 12, or 5 to 10 memberedheteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4heteroatoms) selected from N, O and S and with the remaining ring atomsbeing carbon. Heteroaryl groups do not contain adjacent S and O atoms.In some embodiments, the total number of S and O atoms in the heteroarylgroup is not more than 2. In some embodiments, the total number of S andO atoms in the heteroaryl group is not more than 1. Unless otherwiseindicated, heteroaryl groups may be bound to the parent structure by acarbon or nitrogen atom, as valency permits. For example, “pyridyl”includes 2-pyridyl, 3-pyridyl and 4-pyridyl groups, and “pyrrolyl”includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups. When nitrogen ispresent in a heteroaryl ring, it may, where the nature of the adjacentatoms and groups permits, exist in an oxidized state (i.e., N⁺—O⁻).Additionally, when sulfur is present in a heteroaryl ring, it may, wherethe nature of the adjacent atoms and groups permits, exist in anoxidized state (i.e., S⁺—O⁻ or SO₂). Heteroaryl groups may be monocyclicor polycyclic (e.g., bicyclic, tricyclic).

In some instances, a heteroaryl group is monocyclic. Examples includepyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole,1,2,4-triazole, 1,3,4-triazole), tetrazole, furan, isoxazole, oxazole,oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole),thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine,pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In some instances, both rings of a polycyclic heteroaryl group arearomatic. Examples include indole, isoindole, indazole, benzoimidazole,benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole,benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole,1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine,3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[3,2-b]pyridine, 1H pyrazolo[4,3-b]pyridine,1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine,3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine,1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine,1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine,furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine,[1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine,oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine,[1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine,oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine,[1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine,oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine,[1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine,thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine,[1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine,thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine,[1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine,thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine,[1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine,thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine,[1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, naphthyridine (e.g.,1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine,1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine),imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole,1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

In other instances, polycyclic heteroaryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclicheteroaryl group is bound to the parent structure via an atom in thearomatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylgroup (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered a heteroaryl group, while4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is not considered aheteroaryl group.

“Heterocycloalkyl” indicates a non-aromatic, fully saturated ringhaving, for example, the indicated number of atoms (e.g., 3 to 10, or 3to 7, membered heterocycloalkyl) made up of one or more heteroatoms(e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with theremaining ring atoms being carbon. Heterocycloalkyl groups may bemonocyclic or polycyclic (e.g., bicyclic, tricyclic).

Examples of monocyclic heterocycloalkyl groups include oxiranyl,aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

When nitrogen is present in a heterocycloalkyl ring, it may, where thenature of the adjacent atoms and groups permits, exist in an oxidizedstate (i.e., N⁺—O⁻). Examples include piperidinyl N-oxide andmorpholinyl-N-oxide. Additionally, when sulfur is present in aheterocycloalkyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., S⁺—O⁻ or —SO₂—).Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.

In addition, one ring of a polycyclic heterocycloalkyl group may bearomatic (e.g., aryl or heteroaryl), provided the polycyclicheterocycloalkyl group is bound to the parent structure via anon-aromatic carbon or nitrogen atom. For example, a1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic nitrogen atom) is considered aheterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkyl group.

“Heterocycloalkenyl” indicates a non-aromatic ring having, for example,the indicated number of atoms (e.g., 3 to 10, or 3 to 7, memberedheterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4heteroatoms) selected from N, O and S and with the remaining ring atomsbeing carbon, and at least one double bond derived by the removal of onemolecule of hydrogen from adjacent carbon atoms, adjacent nitrogenatoms, or adjacent carbon and nitrogen atoms of the correspondingheterocycloalkyl. Heterocycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). When nitrogen is present in aheterocycloalkenyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., N⁺—O⁻).Additionally, when sulfur is present in a heterocycloalkenyl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., S⁺—O⁻ or —SO₂—). Examples of heterocycloalkenylgroups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl,2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl,2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl,2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g.,2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl,dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl),tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl,1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g.,1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of apolycyclic heterocycloalkenyl group may be aromatic (e.g., aryl orheteroaryl), provided the polycyclic heterocycloalkenyl group is boundto the parent structure via a non-aromatic carbon or nitrogen atom. Forexample, a 1,2-dihydroquinolin-1-yl group (wherein the moiety is boundto the parent structure via a non-aromatic nitrogen atom) is considereda heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkenyl group.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl (including without limitation C₁-C₄alkyl), cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, unlessotherwise expressly defined, refer respectively to alkyl, cycloalkyl,aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as upto 5, for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine (—NHC(═NH)NH₂), guanidine wherein one or more of the guanidinehydrogens are replaced with a C₁-C₄ alkyl group, —NR^(b)R^(c), halo,cyano, oxo (as a substituent for heterocycloalkyl), nitro, —COR^(b),—CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —SOR^(a),—SO₂R^(a), —SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from C₁-C₆ alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl;

R^(b) is chosen from H, C₁-C₆ alkyl, aryl, and heteroaryl; and

R^(c) is chosen from hydrogen and C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form aheterocycloalkyl group; and

where each C₁-C₆ alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl is optionally substituted with one or more, such as one, two,or three, substituents independently selected from C₁-C₄ alkyl, C₃-C₆cycloalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —OC₁-C₄ haloalkyl, halo, —OH,—NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano,nitro, oxo (as a substituent for heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl,—CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column.

Where the absolute configuration of a single enantiomer is not known theconfiguration has been denoted as E1 (enantiomer 1) and E2 (enantiomer2) and the chiral center labeled with an asterisk. For exampleE1-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideandE2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideare single enantiomers for which the configuration at the chiral centeris not known absolutely.

In addition, such compounds include Z- and E-forms (or cis- andtrans-forms) of compounds with carbon-carbon double bonds. Wherecompounds described herein exist in various tautomeric forms, the term“compound” is intended to include all tautomeric forms of the compound.Such compounds also include crystal forms including polymorphs andclathrates. Similarly, the term “salt” is intended to include alltautomeric forms and crystal forms of the compound.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochloride, phosphate,diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

The term “active agent” is used to indicate a compound or apharmaceutically acceptable salt thereof which has biological activity.In some embodiments, an “active agent” is a compound or pharmaceuticallyacceptable salt thereof having pharmaceutical utility. For example anactive agent may be an anti-neurodegenerative therapeutic.

The term “therapeutically effective amount” means an amount effective,when administered to a human or non-human patient, to provide atherapeutic benefit such as amelioration of symptoms, slowing of diseaseprogression, or prevention of disease e.g., a therapeutically effectiveamount may be an amount sufficient to decrease the symptoms of a diseaseresponsive to inhibition of HDAC activity.

As used herein, the terms “histone deacetylase” and “HDAC” are intendedto refer to any one of a family of enzymes that remove N^(ε)-acetylgroups from the ε-amino groups of lysine residues of a protein (forexample, a histone, or tubulin). Unless otherwise indicated by context,the term “histone” is meant to refer to any histone protein, includingH1, H2A, H2B, H3, H4, and H5, from any species. In some embodiments, thehistone deacetylase is a human HDAC, including, but not limited to,HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10. In some embodiments, theat least one histone deacetylase is selected from HDAC4, HDAC5, HDAC7,and HDAC9. In some embodiments, the histone deacetylase is a class IIaHDAC. In some embodiments, the histone deacetylase is HDAC4. In someembodiments, the histone deacetylase is HDAC5. In some embodiments, thehistone deacetylase is derived from a protozoal or fungal source.

The terms “histone deacetylase inhibitor” and “inhibitor of histonedeacetylase” are intended to mean a compound, or a pharmaceuticallyacceptable salt thereof, described herein which is capable ofinteracting with a histone deacetylase and inhibiting its enzymaticactivity.

The term “a condition or disorder mediated by HDAC” or “a condition ordisorder mediated by histone deacetylase” as used herein refers to acondition or disorder in which HDAC and/or the action of HDAC isimportant or necessary, e.g., for the onset, progress, expression, etc.of that condition, or a condition which is known to be treated by HDACinhibitors (such as, e.g., trichostatin A).

The term “effect” describes a change or an absence of a change in cellphenotype or cell proliferation. “Effect” can also describe a change oran absence of a change in the catalytic activity of HDAC. “Effect” canalso describe a change or an absence of a change in an interactionbetween HDAC and a natural binding partner.

The term “inhibiting histone deacetylase enzymatic activity” is intendedto mean reducing the ability of a histone deacetylase to remove anacetyl group from a protein, such as but not limited to a histone ortubulin. The concentration of inhibitor which reduces the activity of ahistone deacetylase to 50% of that of the uninhibited enzyme isdetermined as the IC₅₀ value. In some embodiments, such reduction ofhistone deacetylase activity is at least 50%, such as at least about75%, for example, at least about 90%. In some embodiments, histonedeacetylase activity is reduced by at least 95%, such as by at least99%. In some embodiments, the compounds and pharmaceutical acceptablesalts thereof described herein have an IC₅₀ value less than 100nanomolar. In some embodiments, the compounds and pharmaceuticalacceptable salts thereof described herein have an IC₅₀ value from 100nanomolar to 1 micromolar. In some embodiments, the compounds andpharmaceutical acceptable salts thereof described herein have an IC₅₀value from 1 to 25 micromolar.

In some embodiments, such inhibition is specific, i.e., the histonedeacetylase inhibitor reduces the ability of a histone deacetylase toremove an acetyl group from a protein at a concentration that is lowerthan the concentration of the inhibitor that is required to produceanother, unrelated biological effect. In some embodiments, theconcentration of the inhibitor required for histone deacetylaseinhibitory activity is at least 2-fold lower, such as at least 5-foldlower, for example, at least 10-fold lower, such as at least 20-foldlower than the concentration required to produce an unrelated biologicaleffect.

“Treatment” or “treating” means any treatment of a disease state in apatient, including

a) preventing the disease, that is, causing the clinical symptoms of thedisease not to develop;

b) inhibiting the disease;

c) slowing or arresting the development of clinical symptoms; and/or

d) relieving the disease, that is, causing the regression of clinicalsymptoms.

“Subject” or “patient’ refers to an animal, such as a mammal, that hasbeen or will be the object of treatment, observation or experiment. Themethods described herein may be useful in both human therapy andveterinary applications. In some embodiments, the subject is a mammal;and in some embodiments the subject is human.

Provided is a compound of Formula I, or a pharmaceutically acceptablesalt thereof,

wherein:

-   R¹ is chosen from —C(O)NH(OH) and —N(OH)C(O)R⁹;-   R² is chosen from aryl, heteroaryl, and heterocycloalkyl, each of    which is optionally substituted with 1 to 3 substituents    independently chosen from halo, alkyl, cycloalkyl, haloalkyl,    hydroxyl, alkoxy, and nitrile;-   A is chosen from aryl and heteroaryl;-   R³ and R⁴ are independently chosen from hydrogen, alkyl, halo,    NHSO₂R¹⁰, C(O)NR¹¹R¹², NR¹¹R¹², nitrile, cycloalkyl,    heterocycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl, each    of which is optionally substituted with 1 to 3 substituents    independently chosen from halo, alkyl, cycloalkyl, haloalkyl,    hydroxyl, alkoxy, aryl, heteroaryl, and nitrile, wherein alkyl and    alkoxy are optionally substituted with amino, (alkyl)amino or    di(alkyl)amino;-   for each occurrence, R⁵, R⁶, R⁷, and R⁸ are independently chosen    from hydrogen and lower alkyl;-   R⁹ is chosen from hydrogen and lower alkyl;-   R¹⁰ is chosen from lower alkyl, cycloalkyl, heterocycloalkyl, aryl,    and heteroaryl;-   R¹¹ and R¹² are independently chosen from hydrogen, lower alkyl,    alkoxy, lower haloalkyl and cycloalkyl wherein alkyl and alkoxy are    optionally substituted with amino, (alkyl)amino or di(alkyl)amino,    and-   m and m′ are independently chosen from 0, 1, 2, 3 and 4, provided    that 2 (m+m′) 4.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is chosen from compounds of Formula II, or apharmaceutically acceptable salt thereof:

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from phenyl optionally substitutedwith one or two substituents independently chosen from lower alkyl,lower haloalkyl, lower alkoxy, lower haloalkoxy, and halo.

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from phenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-chloro-2-fluorophenyl, 2,6-difluorophenyl, 2,5-dimethylphenyl,2,6-dimethylphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-methylphenyl,2,4-difluorophenyl, 4-(difluoromethoxy)phenyl, and3-fluoro-2-methylphenyl.

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from pyridin-2-yl, pyridin-4-yl,and pyrazin-2-yl, each of which is optionally substituted with one ortwo substituents independently chosen from lower alkyl and halo.

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from 5-fluoropyridin-2-yl,pyrazin-2-yl, and 3-methylpyridin-4-yl.

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from cyclopropyl and cyclopentyl,each of which is optionally substituted with one or two substituentsindependently chosen from lower alkyl and halo.

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from cyclopropyl and cyclopentyl.

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from isopropyl.

In some embodiments of compounds of Formula II, or a pharmaceuticallyacceptable salt thereof, R⁴ is hydrogen.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is chosen from compounds of Formula III, or apharmaceutically acceptable salt thereof:

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from lower alkyl, lower haloalkyl,and aralkyl optionally substituted with halo.

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R³ is chosen form methyl,2,2,2,-trifluoroethyl, and 4-fluorobenzyl.

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from phenyl optionally substitutedwith one or two substituents independently chosen from lower alkyl,lower haloalkyl, lower alkoxy, lower haloalkoxy, and halo.

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from 2-fluorophenyl,4-(difluoromethoxy)phenyl, 4-fluoro-2-methylphenyl, and 3-methylphenyl.

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from pyridin-2-yl andpyridin-4-yl, each of which is optionally substituted with one or twosubstituents independently chosen from lower alkyl and halo.

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from 3-methylpyridin-4-yl,3-chloropyridin-2-yl, and 3-fluoropyridin-2-yl.

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R⁴ is chosen from hydrogen, cyclopropyl, andphenyl optionally substituted with halo.

In some embodiments of compounds of Formula III, or a pharmaceuticallyacceptable salt thereof, R⁴ is hydrogen.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is chosen from compounds of Formula IV, or apharmaceutically acceptable salt thereof:

In some embodiments of compounds of Formula IV, or a pharmaceuticallyacceptable salt thereof, R³ is hydrogen.

In some embodiments of compounds of Formula IV, or a pharmaceuticallyacceptable salt thereof, R⁴ is cyclopropyl.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is chosen from compounds of Formula V, or apharmaceutically acceptable salt thereof:

In some embodiments of compounds of Formula V, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from

hydrogen,

cycloalkyl optionally substituted with one or two groups independentlychosen from halo, lower alkyl, lower haloalkyl, and lower alkoxy,

heteroaryl optionally substituted with one or two groups independentlychosen from halo, lower alkyl, lower haloalkyl, and lower alkoxy,

phenyl optionally substituted with one or two groups independentlychosen from halo, lower alkyl, lower haloalkyl, and lower alkoxy,

benzyl optionally substituted on the aromatic portion with one or twogroups independently chosen from halo, lower alkyl, lower haloalkyl, andlower alkoxy, and

—NHS(O)₂R¹⁰ where R¹⁰ is chosen from phenyl.

In some embodiments of compounds of Formula V, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from hydrogen, cyclopropyl, phenyloptionally substituted with one or two groups independently chosen fromfluoro and methyl, pyrimidin-5-yl, 1H-pyrazol-5-yl optionallysubstituted with methyl, 1H-pyrazol-4-yl optionally substituted withmethyl, pyridin-2-yl optionally substituted with methoxy, benzyloptionally substituted on the aromatic portion with trifluoromethyl, and—NHS(O)₂R¹⁰ where R¹⁰ is chosen from phenyl.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is chosen from compounds of Formula VI, or apharmaceutically acceptable salt thereof:

In some embodiments of compounds of Formula VI, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from hydrogen, lower alkyl, lowerhaloalkyl, cycloalkyl, phenyl optionally substituted with halo, andheteroaryl.

In some embodiments of compounds of Formula VI, or a pharmaceuticallyacceptable salt thereof, R³ is chosen from hydrogen, trifluoromethyl,cyclopropyl, phenyl optionally substituted with halo, and pyridin-3-yl.

In some embodiments of compounds of Formula VI, or a pharmaceuticallyacceptable salt thereof, R⁴ is hydrogen.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is chosen from compounds of Formula VII, or apharmaceutically acceptable salt thereof:

In some embodiments of compounds of Formula VII, or a pharmaceuticallyacceptable salt thereof, R³ is hydrogen.

In some embodiments of compounds of Formula VII, or a pharmaceuticallyacceptable salt thereof, R⁴ is hydrogen.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is chosen from compounds of Formula VIII, or apharmaceutically acceptable salt thereof:

In some embodiments of compounds of Formula VIII, or a pharmaceuticallyacceptable salt thereof, R³ is phenyl optionally substituted with 1 to 3substituents independently chosen from halo, alkyl, cycloalkyl,haloalkyl, hydroxyl, and alkoxy.

In some embodiments of compounds of Formula VIII, or a pharmaceuticallyacceptable salt thereof, R³ is phenyl.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, R² is chosen from aryloptionally substituted with 1 to 3 substituents independently chosenfrom halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, R² is chosen from phenyloptionally substituted with 1 to 3 substituents independently chosenfrom halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, R² is chosen from phenyloptionally substituted with 1 to 3 substituent independently chosen fromhalo and alkyl.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, R² is chosen from phenyl and3-fluoro-2-methylphenyl.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, R² is 3-fluoro-2-methylphenyl.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, m is 1 and m′ is 1.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, m is 1 and m′ is 2.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, m is 0 and m′ is 2.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, m is 2 and m′ is 2.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, R¹ is —N(OH)C(O)R⁹. In someembodiments, R⁹ is lower alkyl.

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, R¹ is chosen from —C(O)NH(OH).

In some embodiments of compounds of Formula I-VIII, or apharmaceutically acceptable salt thereof, for each occurrence, R⁵, R⁶,R⁷, and R⁸ are hydrogen.

Also provided is a compound of Formula I chosen from

-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2-yl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(pyrazin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-2-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide    and    5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide    and    5-(3-fluoro-2-methylphenyl)-2-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide;-   6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;-   2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;-   6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;-   6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;-   6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide;-   2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide;-   6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxamide;-   (S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;-   (R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;-   (R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;-   (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;-   (S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-isopropyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (R)-4-(3-Fluoro-2-methyl-phenyl)-1-phenyl-5,6-dihydrocyclopenta[c]pyrazole-4-carbohydroxamic    acid;-   (S)-6-(3-Fluoro-2-methyl-phenyl)-2-(4-fluorophenyl)-5,7-dihydrocyclopenta[d]pyrimidine-6-carbohydroxamic    acid;-   (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;-   (R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;-   (S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;-   (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;-   E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;-   (S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;-   E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   E2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;-   (S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;-   (R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   E1-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide;-   E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide;-   2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide;-   2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxamide;-   E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;-   E2-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;-   N-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;-   E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide;-   E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide;-   N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide;-   (R)-4-(3-Fluoro-2-methylphenyl)-2-(2-fluorobenzyl)-N-hydroxy-2,4,5,tetrahydrocyclopenta[c]pyrazole-4-carboxamide;-   (S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;-   (R)-1-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;-   (R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;    and-   (R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide,-   or a pharmaceutically acceptable salt thereof.

Methods for obtaining the compounds, or pharmaceutically acceptablesalts thereof, described herein will be apparent to those of ordinaryskill in the art, suitable procedures being described, for example, inexamples below, and in the references cited herein.

Also provided is a method for inhibiting at least one histonedeacetylase. In some embodiments, at least one histone deacetylase is aclass IIa HDAC. In some embodiments, at least one histone deacetylase isselected from HDAC4, HDAC5, HDAC7, and HDAC5. In some embodiments, theinhibition is in a cell. In some embodiments, the compound, orpharmaceutically acceptable salt thereof, described herein is selectivefor inhibiting at least one class II histone deacetylase. In someembodiments, the compound, or pharmaceutically acceptable salt thereof,described herein is a selective inhibitor of HDAC4 and/or HDAC5.

Also provided is a method of treating a condition or disorder mediatedby HDAC in a subject in need of such a treatment, comprisingadministering to the subject a therapeutically effective amount of atleast one compound, or pharmaceutically acceptable salt thereof,described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a neurodegenerative pathology. Accordingly, also provided is amethod of treating a neurodegenerative pathology mediated by HDAC in asubject in need of such a treatment, comprising administering to thesubject a therapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein.

In some embodiments, the neurodegenerative pathology is chosen fromAlzheimer's disease, Parkinson's disease, neuronal intranuclearinclusion disease (NIID), Dentatorubral pallidolusyian atrophy (DRPLA),Friedreich's ataxia, Rubenstein-Taubi Syndrome, and polyglutaminediseases such as Huntington's disease; spinocerebellar ataxia 1 (SCA 1),spinocerebellar ataxia 7 (SCA 7), seizures, striatonigral degeneration,progressive supranuclear palsy, torsion dystonia, spasmodic torticollis,dyskinesis, familial tremor, Gilles de la Tourette syndrome, diffuseLewy body disease, progressive supranuclear palsy, Pick's disease,primary lateral sclerosis, progressive neural muscular atrophy, spinalmuscular atrophy, hypertrophic interstitial polyneuropathy, retinitispigmentosa, hereditary optic atrophy, hereditary spastic paraplegia,Shy-Drager syndrome, Kennedy's disease, protein-aggregation-relatedneurodegeneration, Machado-Joseph's disease, spongiform encephalopathy,prion-related disease, multiple sclerosis (MS), progressive supranuclearpalsy (Steel-Richardson-Olszewski disease), Hallervorden-Spatz disease,progressive familial myoclonic epilepsy, cerebellar degeneration, motorneuron disease, Werdnig-Hoffman disease, Wohlfart-Kugelberg-Welanderdisease, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, retinitispigmentosa, Leber's disease, progressive systemic sclerosis,dermatomyositis, and mixed connective tissue disease.

In some embodiments, the neurodegenerative pathology is an acute orchronic degenerative disease of the eye. Acute or chronic degenerativediseases of the eye include glaucoma, dry age-related maculardegeneration, retinitis pigmentosa and other forms of heredodegenerativeretinal disease, retinal detachment, macular pucker, ischemia affectingthe outer retina, cellular damage associated with diabetic retinopathyand retinal ischemia, damage associated with laser therapy, ocularneovascular, diabetic retinopathy, rubeosis iritis, uveitis, Fuch'sheterochromatic iridocyclitis, neovascular glaucoma, cornealneovascularization, retinal ischemia, choroidal vascular insufficiency,choroidal thrombosis, carotid artery ischemia, contusive ocular injury,retinopathy of permaturity, retinal vein occlusion, proliferativevitreoretinopathy, corneal angiogenesis, retinal microvasculopathy, andretinal eduema.

In some embodiments, the condition or disorder mediated by HDACcomprises a fibrotic disease such as liver fibrosis, cystic fibrosis,cirrhosis, and fibrotic skin diseases, e.g., hypertrophic scars, keloid,and Dupuytren's contracture. Accordingly, also provided is a method oftreating a fibrotic disease mediated by HDAC in a subject in need ofsuch a treatment, comprising administering to the subject atherapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a psychological disorder, such as depression, bipolar diseaseand dementia. In some embodiments, the condition or disorder mediated byHDAC comprises depression. Accordingly, also provided is a method oftreating a psychological disorder, such as depression, mediated by HDACin a subject in need of such a treatment, comprising administering tothe subject a therapeutically effective amount of at least one compound,or pharmaceutically acceptable salt thereof, described herein. In someembodiments, the depression is chosen from major depressive disorder,and bipolar disorder.

In some embodiments, the condition or disorder mediated by HDACcomprises anxiety. Accordingly, also provided is a method of treating ananxiety mediated by HDAC in a subject in need of such a treatment,comprising administering to the subject a therapeutically effectiveamount of at least one compound, or pharmaceutically acceptable saltthereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises schizophrenia. Accordingly, also provided is a method oftreating a schizophrenia mediated by HDAC in a subject in need of such atreatment, comprising administering to the subject a therapeuticallyeffective amount of at least one compound, or pharmaceuticallyacceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a motor neuron disease, muscle atrophy/muscle wastingdisorders, or amyotrophic lateral sclerosis (ALS). Accordingly, alsoprovided is a method of treating a motor neuron disease, muscleatrophy/muscle wasting disorders, or amyotrophic lateral sclerosis (ALS)mediated by HDAC in a subject in need of such a treatment, comprisingadministering to the subject a therapeutically effective amount of atleast one compound, or pharmaceutically acceptable salt thereof,described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a cardiovascular condition. Accordingly, also provided is amethod of treating a cardiovascular condition mediated by HDAC in asubject in need of such a treatment, comprising administering to thesubject a therapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein. In someembodiments, the cardiovascular condition is chosen from cardiomyopathy,cardiac hypertrophy, myocardial ischemia, heart failure, cardiacrestenosis, and arteriosclerosis.

In some embodiments, the condition or disorder mediated by HDACcomprises cancer. Accordingly, also provided is a method of treatingcancer mediated by HDAC in a subject in need of such a treatment,comprising administering to the subject a therapeutically effectiveamount of at least one compound, or pharmaceutically acceptable saltthereof, described herein. In some embodiments, the cancer is chosenfrom lymphoma, pancreatic cancer, colorectal cancer, hepatocellularcarcinoma, Waldenstrom macroglobulinemia, hormone refractory cancer ofthe prostate, and leukaemia, breast cancer, lung cancer, ovarian cancer,prostate cancer, head and neck cancer, renal cancer, gastric cancer,brain cancer, B-cell lymphoma, peripheral T-cell lymphoma, and cutaneousT-cell lymphoma. In some further embodiments, the cancer is chosen fromthe following cancer types. Cardiac: sarcoma (angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamouscell, undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma,hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma;and the sensitization of tumors to radiotherapy by administering thecompound according to the invention before, during or after irradiationof the tumor for treating cancer.

In some embodiments, the condition or disorder mediated by HDACcomprises a condition or disorder treatable by immune modulation.Accordingly, also provided is a method of treating a condition ordisorder treatable by immune modulation mediated by HDAC in a subject inneed of such a treatment, comprising administering to the subject atherapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein. In someembodiments, the condition or disorder treatable by immune modulation ischosen from asthma, irritable bowel syndrome, Crohn's disease,ulcerative colitis, bowel motility disorders, hypertension, rheumatoidarthritis, osteoarthritis, juvenile chronic arthritis, graft versus hostdisease, psoriasis, spondyloarthropathy, inflammatory bowel disease,alcoholic hepatitis, Sjogren's syndrome, ankylosing spondylitis,membranous glomerulopathy, discogenic pain, systemic lupuserythematosus, allergic bowel disease, coeliac disease, bronchitis,cystic fibrosis, rheumatoid spondylitis, osteoarthritis, uveitis, intis,and conjunctivitis, ischemic bowel disease, psoriasis, eczema,dermatitis, septic arthritis, gout, pseudogout, juvenile arthritis,Still's disease, Henoch-Schonlein purpura, psoriatic arthritis, myalgia,reactive arthritis (Reiter's syndrome), hemochromatosis, Wegener'sgranulomatosis, familial Mediterranean fever (FMF), HBDS(hyperimmunoglobulinemia D and periodic fever syndrome), TRAPS(TNF-alpha receptor associated periodic fever syndrome), chronicobstructive pulmonary disease, neonatal-onset multisystem inflammatorydisease (NOMID), cryopyrin-associated periodic syndrome (CAPS), andfamilial cold autoinflammatory syndrome (FCAS).

In some embodiments, the condition or disorder mediated by HDACcomprises an allergic disease. Accordingly, also provided is a method oftreating an allergic disease, mediated by HDAC in a subject in need ofsuch a treatment, comprising administering to the subject atherapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein. Allergicdiseases include, but are not limited to, respiratory allergic diseasessuch as allergic rhinitis, hypersensitivity lung diseases,hypersensitivity pneumonitis, eosinophilic pneumonias, Loeffler'ssyndrome, chronic eosinophilic pneumonia, delayed-type hypersensitivity,interstitial lung diseases (ILD), idiopathic pulmonary fibrosis,polymyositis, dermatomyositis, systemic anaphylaxis, drug allergies(e.g., to penicillin or cephalosporins), and insect sting allergies.

In some embodiments, the condition or disorder mediated by HDACcomprises an infectious disease such as a fungal infection, bacterialinfection, viral infection, and protozoal infection, e.g., malaria,giardiasis, leishmaniasis, Chaga's disease, dysentery, toxoplasmosis,and coccidiosis. In some embodiments, the condition or disorder mediatedby HDAC comprises malaria. Accordingly, also provided is a method oftreating an infectious disease, such as malaria, mediated by HDAC in asubject in need of such a treatment, comprising administering to thesubject a therapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises autism or Rett syndrome. Accordingly, also provided is amethod of treating autism or Rett syndrome mediated by HDAC in a subjectin need of such a treatment, comprising administering to the subject atherapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a hematological disorder such as thalassemia, anemia, andsickle cell anemia. Accordingly, also provided is a method of treating ahematological disorder mediated by HDAC in a subject in need of such atreatment, comprising administering to the subject a therapeuticallyeffective amount of at least one compound, or pharmaceuticallyacceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a metabolic disease such as prediabetes or diabetes (type I orII). Accordingly, also provided is a method of treating a metabolicdisease, such as prediabetes or diabetes (type I or II), mediated byHDAC in a subject in need of such a treatment, comprising administeringto the subject a therapeutically effective amount of at least onecompound, or pharmaceutically acceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a disorder that may also be treated by progenitor/stem cellbased therapies such as: disorders related to diabetes (organ failure,cerrosis, and hepatitis); central nervous system (CNS) disordersassociated with dysregulation of progenitor cells in the brain (e.g.,post-traumatic stress disorder (PTSD); tumors (e.g., retinoblastomas);disorders affecting oligodendrycoyte progenitor cells (e.g.,astrocytomas and ependimal cell tumors); multiple sclerosis;demyelinating disorders such as the leukodystrophies; neuropathiesassociated with white matter loss; and cerebellar disorders such asataxia; and olfactory progenitor disorders (e.g., anosmic conditions).Accordingly, also provided is a method of treating a disorder that ismediated by HDAC in a subject in need of such a treatment, comprisingadministering to the subject a therapeutically effective amount of atleast one compound, or pharmaceutically acceptable salt thereof,described herein, either before, during, or after a treatment withprogenitor/stem cell based therapies.

In some embodiments, the condition or disorder mediated by HDACcomprises a disorder related to the proliferation of epithelial andmesenchymal cells (e.g., tumors, wound healing, and surgeries).Accordingly, also provided is a method of treating a disorder related tothe proliferation of epithelial and mesenchymal cells that is mediatedby HDAC in a subject in need of such a treatment, comprisingadministering to the subject a therapeutically effective amount of atleast one compound, or pharmaceutically acceptable salt thereof,described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a disorder related to the proliferation of bone progenitors(e.g., osteoblasts and osteoclasts), disorders related to hair andepidermal progenitors (e.g., hair loss, cutaneous tumors, skinregeneration, burns, and cosmetic surgery); and disorders related tobone loss during menopause. Accordingly, also provided is a method oftreating disorders related to the proliferation of bone progenitors,disorders related to hair and epidermal progenitors, or disordersrelated to bone loss that are mediated by HDAC in a subject in need ofsuch a treatment, comprising administering to the subject atherapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDAC is aviral disorder for which blood cells become sensitized to othertreatments after HDAC inhibition, following administering to the subjecta therapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, as described herein.

In some embodiments, the condition or disorder mediated by HDAC is animmune disorder that may be co-treated with TNFα or other immunemodulators, upon administering to the subject a therapeuticallyeffective amount of at least one compound, or pharmaceuticallyacceptable salt thereof, as described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a graft rejection or transplant rejection. Accordingly, alsoprovided is a method of treating a disorder related to a graft rejectionor a transplant rejection that is mediated by HDAC in a subject in needof such a treatment, comprising administering to the subject atherapeutically effective amount of at least one compound, orpharmaceutically acceptable salt thereof, described herein.

In some embodiments, the condition or disorder mediated by HDACcomprises a blood pressure disorder related to nitric oxide (NO)regulation (e.g., hypertension, erectile dysfunction, asthma; and oculardisorders as glaucoma). Accordingly, also provided is a method oftreating a blood pressure disorder related to nitric oxide (NO)regulation that is mediated by HDAC in a subject in need of such atreatment, comprising administering to the subject a therapeuticallyeffective amount of at least one compound, or pharmaceuticallyacceptable salt thereof, described herein. In some embodiments, thecondition or disorder is a cardiac hypertrophic disorder. Accordingly,also provided is a method of treating a cardiac hypertrophic disorderthat is mediated by HDAC in a subject in need of such a treatment,comprising administering to the subject a therapeutically effectiveamount of at least one compound, or pharmaceutically acceptable saltthereof, described herein.

Also provided are methods of treatment in which at least one compound,or pharmaceutically acceptable salt thereof, described herein is theonly active agent given to the subject and also includes methods oftreatment in which at least one compound, or pharmaceutically acceptablesalt thereof, described herein is given to the subject in combinationwith one or more additional active agents.

In general, the compounds, or pharmaceutically acceptable salts thereof,described herein will be administered in a therapeutically effectiveamount by any of the accepted modes of administration for agents thatserve similar utilities. The actual amount of the compound, i.e., theactive ingredient, will depend upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, and other factors well known to the skilled artisan. Thedrug can be administered at least once a day, such as once or twice aday.

In some embodiments, the compounds, or pharmaceutically acceptable saltsthereof, described herein are administered as a pharmaceuticalcomposition. Accordingly, provided are pharmaceutical compositionscomprising at least one compound, or pharmaceutically acceptable saltthereof, described herein, together with at least one pharmaceuticallyacceptable vehicle chosen from carriers, adjuvants, and excipients.

Pharmaceutically acceptable vehicles must be of sufficiently high purityand sufficiently low toxicity to render them suitable for administrationto the animal being treated. The vehicle can be inert or it can possesspharmaceutical benefits. The amount of vehicle employed in conjunctionwith the compound, or pharmaceutically acceptable salt thereof, issufficient to provide a practical quantity of material foradministration per unit dose of the compound, or pharmaceuticallyacceptable salt thereof.

Exemplary pharmaceutically acceptable carriers or components thereof aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; synthetic oils; vegetable oils,such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil;polyols such as propylene glycol, glycerine, sorbitol, mannitol, andpolyethylene glycol; alginic acid; phosphate buffer solutions;emulsifiers, such as the TWEENS; wetting agents, such sodium laurylsulfate; coloring agents; flavoring agents; tableting agents;stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions.

Optional active agents may be included in a pharmaceutical composition,which do not substantially interfere with the activity of the compound,or pharmaceutically acceptable salt thereof, described herein.

Effective concentrations of at least one compound, or pharmaceuticallyacceptable salt thereof, described herein are mixed with a suitablepharmaceutically acceptable vehicle. In instances in which the compound,or pharmaceutically acceptable salt thereof, exhibits insufficientsolubility, methods for solubilizing compounds may be used. Such methodsare known to those of skill in this art, and include, but are notlimited to, using cosolvents, such as dimethylsulfoxide (DMSO), usingsurfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate.

Upon mixing or addition of a compound, or pharmaceutically acceptablesalt thereof, described herein, the resulting mixture may be a solution,suspension, emulsion or the like. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound, or pharmaceuticallyacceptable salt thereof, in the chosen vehicle. The effectiveconcentration sufficient for ameliorating the symptoms of the diseasetreated may be empirically determined

The compounds, or pharmaceutically acceptable salts thereof, describedherein may be administered orally, topically, parenterally,intravenously, by intramuscular injection, by inhalation or spray,sublingually, transdermally, via buccal administration, rectally, as anophthalmic solution, or by other means, in dosage unit formulations.

Pharmaceutical compositions may be formulated for oral use, such as forexample, tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, hard or soft capsules, orsyrups or elixirs. Pharmaceutical compositions intended for oral use maybe prepared according to any method known to the art for the manufactureof pharmaceutical compositions and such compositions may contain one ormore agents, such as sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide pharmaceuticallyelegant and palatable preparations. In some embodiments, oralpharmaceutical compositions contain from 0.1 to 99% of at least onecompound, or pharmaceutically acceptable salt thereof, described herein.In some embodiments, oral pharmaceutical compositions contain at least5% (weight %) of at least one compound, or pharmaceutically acceptablesalt thereof, described herein. Some embodiments contain from 25% to 50%or from 5% to 75% of at least one compound, or pharmaceuticallyacceptable salt thereof, described herein.

Orally administered pharmaceutical compositions also include liquidsolutions, emulsions, suspensions, powders, granules, elixirs,tinctures, syrups, and the like. The pharmaceutically acceptablecarriers suitable for preparation of such compositions are well known inthe art. Oral pharmaceutical compositions may contain preservatives,flavoring agents, sweetening agents, such as sucrose or saccharin,taste-masking agents, and coloring agents.

Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol or sucrose. Such pharmaceutical compositions may alsocontain a demulcent.

The compound, or pharmaceutically acceptable salt thereof, describedherein can be incorporated into oral liquid preparations such as aqueousor oily suspensions, solutions, emulsions, syrups, or elixirs, forexample. Moreover, pharmaceutical compositions containing these at leastone compound, or pharmaceutically acceptable salt thereof, can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can contain conventionaladditives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminum stearate gel, and hydrogenated ediblefats), emulsifying agents (e.g., lecithin, sorbitan monsoleate, oracacia), non-aqueous vehicles, which can include edible oils (e.g.,almond oil, fractionated coconut oil, silyl esters, propylene glycol andethyl alcohol), and preservatives (e.g., methyl or propylp-hydroxybenzoate and sorbic acid).

For a suspension, typical suspending agents include methylcellulose,sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents; may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These pharmaceutical compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example olive oilor peanut oil, or a mineral oil, for example liquid paraffin or mixturesof these. Suitable emulsifying agents may be naturally-occurring gums,for example gum acacia or gum tragacanth, naturally-occurringphosphatides, for example soy bean, lecithin, and esters or partialesters derived from fatty acids and hexitol, anhydrides, for examplesorbitan monoleate, and condensation products of the said partial esterswith ethylene oxide, for example polyoxyethylene sorbitan monoleate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Tablets typically comprise conventional pharmaceutically acceptableadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, can beuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability.

Such pharmaceutical compositions may also be coated by conventionalmethods, typically with pH or time-dependent coatings, such that thecompound, or pharmaceutically acceptable salt thereof, is released inthe gastrointestinal tract in the vicinity of the desired topicalapplication, or at various times to extend the desired action. Suchdosage forms typically include, but are not limited to, one or more ofcellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes andshellac.

Pharmaceutical compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin or olive oil.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents that have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable vehicle, for example asa solution in 1,3-butanediol. Among the acceptable vehicles that may beemployed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid can be useful in the preparation ofinjectables.

The compound, or pharmaceutically acceptable salt thereof, describedherein may be administered parenterally in a sterile medium. Parenteraladministration includes subcutaneous injections, intravenous,intramuscular, intrathecal injection or infusion techniques. Thecompound, or pharmaceutically acceptable salt thereof, described herein,depending on the vehicle and concentration used, can either be suspendedor dissolved in the vehicle. Advantageously, adjuvants such as localanesthetics, preservatives and buffering agents can be dissolved in thevehicle. In many pharmaceutical compositions for parenteraladministration the carrier comprises at least 90% by weight of the totalcomposition. In some embodiments, the carrier for parenteraladministration is chosen from propylene glycol, ethyl oleate,pyrrolidone, ethanol, and sesame oil.

The compound, or pharmaceutically acceptable salt thereof, describedherein may also be administered in the form of suppositories for rectaladministration of the drug. These pharmaceutical compositions can beprepared by mixing the drug with a suitable non-irritating excipientthat is solid at ordinary temperatures but liquid at rectal temperatureand will therefore melt in the rectum to release the drug. Suchmaterials include cocoa butter and polyethylene glycols.

The compound, or pharmaceutically acceptable salt thereof, describedherein may be formulated for local or topical application, such as fortopical application to the skin and mucous membranes, such as in theeye, in the form of gels, creams, and lotions and for application to theeye. Topical pharmaceutical compositions may be in any form including,for example, solutions, creams, ointments, gels, lotions, milks,cleansers, moisturizers, sprays, skin patches, and the like.

Such solutions may be formulated as 0.01%-10% isotonic solutions, pH5-7, with appropriate salts. The compound, or pharmaceuticallyacceptable salt thereof, described herein may also be formulated fortransdermal administration as a transdermal patch.

Topical pharmaceutical compositions comprising at least one compound, orpharmaceutically acceptable salt thereof, described herein can beadmixed with a variety of carrier materials well known in the art, suchas, for example, water, alcohols, aloe vera gel, allantoin, glycerine,vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristylpropionate, and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows.

Representative emollients include stearyl alcohol, glycerylmonoricinoleate, glyceryl monostearate, propane-1,2-diol,butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate,stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol,isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetylalcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate,iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butylstearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil,coconut oil, arachis oil, castor oil, acetylated lanolin alcohols,petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid,isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, andmyristyl myristate; propellants, such as propane, butane, iso-butane,dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such asethyl alcohol, methylene chloride, iso-propanol, castor oil, ethyleneglycol monoethyl ether, diethylene glycol monobutyl ether, diethyleneglycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide,tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, andgelatin; and powders, such as chalk, talc, fullers earth, kaolin,starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium smectites, trialkyl aryl ammonium smectites, chemicallymodified magnesium aluminium silicate, organically modifiedmontmorillonite clay, hydrated aluminium silicate, fumed silica,carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethyleneglycol monostearate.

The compound, or pharmaceutically acceptable salt thereof, describedherein may also be topically administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles, and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Other pharmaceutical compositions useful for attaining systemic deliveryof the compound, or pharmaceutically acceptable salt thereof, includesublingual, buccal and nasal dosage forms. Such pharmaceuticalcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol, and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethylcellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Pharmaceutical compositions for inhalation typically can be provided inthe form of a solution, suspension or emulsion that can be administeredas a dry powder or in the form of an aerosol using a conventionalpropellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).

The pharmaceutical compositions may also optionally comprise an activityenhancer. The activity enhancer can be chosen from a wide variety ofmolecules that function in different ways to enhance or be independentof therapeutic effects of the compound, or pharmaceutically acceptablesalt thereof, described herein. Particular classes of activity enhancersinclude skin penetration enhancers and absorption enhancers.

Pharmaceutical compositions may also contain additional active agentsthat can be chosen from a wide variety of molecules, which can functionin different ways to enhance the therapeutic effects of at least onecompound, or pharmaceutically acceptable salt thereof, described herein.These optional other active agents, when present, are typically employedin the pharmaceutical compositions at a level ranging from 0.01% to 15%.Some embodiments contain from 0.1% to 10% by weight of the composition.Other embodiments contain from 0.5% to 5% by weight of the composition.

Also provided are packaged pharmaceutical compositions. Such packagedcompositions include a pharmaceutical composition comprising at leastone compound, or pharmaceutically acceptable salt thereof, describedherein, and instructions for using the composition to treat a subject(typically a human patient). In some embodiments, the instructions arefor using the pharmaceutical composition to treat a subject suffering acondition or disorder mediated by HDAC. The packaged pharmaceuticalcomposition can include providing prescribing information; for example,to a patient or health care provider, or as a label in a packagedpharmaceutical composition. Prescribing information may include forexample efficacy, dosage and administration, contraindication andadverse reaction information pertaining to the pharmaceuticalcomposition.

In all of the foregoing the compound, or pharmaceutically acceptablesalt thereof, can be administered alone, as mixtures, or in combinationwith other active agents.

The methods described herein include methods for treating Huntington'sdisease, including treating memory and/or cognitive impairmentassociated with Huntington's disease, comprising administering to asubject, simultaneously or sequentially, at least one compound, orpharmaceutically acceptable salt thereof, described herein and one ormore additional agents used in the treatment of Huntington's diseasesuch as, but not limited to, Amitriptyline, Imipramine, Despiramine,Nortriptyline, Paroxetine, Fluoxetine, Setraline, Terabenazine,Haloperidol, Chloropromazine, Thioridazine, Sulpride, Quetiapine,Clozapine, and Risperidone. In methods using simultaneousadministration, the agents can be present in a combined composition orcan be administered separately. As a result, also provided arepharmaceutical compositions comprising at least one compound, orpharmaceutically acceptable salt thereof, described herein and one ormore additional pharmaceutical agents used in the treatment ofHuntington's disease such as, but not limited to, Amitriptyline,Imipramine, Despiramine, Nortriptyline, Paroxetine, Fluoxetine,Setraline, Terabenazine, Haloperidol, Chloropromazine, Thioridazine,Sulpride, Quetiapine, Clozapine, and Risperidone. Similarly, alsoprovided are packaged pharmaceutical compositions containing apharmaceutical composition comprising at least one compound, orpharmaceutically acceptable salt thereof, described herein, and anothercomposition comprising one or more additional pharmaceutical agents usedin the treatment of Huntington's disease such as, but not limited to,Amitriptyline, Imipramine, Despiramine, Nortriptyline, Paroxetine,Fluoxetine, Setraline, Terabenazine, Haloperidol, Chloropromazine,Thioridazine, Sulpride, Quetiapine, Clozapine, and Risperidone.

Also provided are methods for Alzheimer's disease, including treatingmemory and/or cognitive impairment associated with Alzheimer's disease,comprising administering to a subject, simultaneously or sequentially,at least one compound, or pharmaceutically acceptable salt thereof,described herein and one or more additional agents used in the treatmentof Alzheimer's disease such as, but not limited to, Reminyl, Cognex,Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Clioquinol.In methods using simultaneous administration, the agents can be presentin a combined composition or can be administered separately. Alsoprovided are pharmaceutical compositions comprising at least onecompound, or pharmaceutically acceptable salt thereof, described herein,and one or more additional pharmaceutical agents used in the treatmentof Alzheimer's disease such as, but not limited to, Reminyl, Cognex,Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Clioquinol.Similarly, also provided are packaged pharmaceutical compositionscontaining a pharmaceutical composition comprising at least onecompound, or pharmaceutically acceptable salt thereof, described herein,and another composition comprising one or more additional pharmaceuticalagents used in the treatment of Alzheimer's disease such as, but notlimited to Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin,Eldepryl, Estrogen and Clioquinol.

Also provided are methods for treating cancer comprising administeringto a subject, simultaneously or sequentially, at least one compound, orpharmaceutically acceptable salt thereof, described herein and one ormore additional agents used in the treatment of cancer such as, but notlimited to, the following categories of anti-tumor agents

(i) other cell cycle inhibitory agents that work by the same ordifferent mechanisms from those defined hereinbefore, for example cyclindependent kinase (CDK) inhibitors, in particular CDK2 inhibitors;

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (forexample megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrazole, vorazole, exemestane), antiprogestogens,antiandrogens (for example flutamide, nilutamide, bicalutamide,cyproterone acetate), LHRH agonists and antagonists (for examplegoserelin acetate, luprolide), inhibitors of testosterone5.alpha.-dihydroreductase (for example finasteride), anti-invasionagents (for example metalloproteinase inhibitors like marimastat andinhibitors of urokinase plasminogen activator receptor function) andinhibitors of growth factor function, (such growth factors include forexample vascular endothelial growth factor, epithelial growth factor,platelet derived growth factor and hepatocyte growth factor suchinhibitors include growth factor antibodies, growth factor receptorantibodies, tyrosine kinase inhibitors and serine/threonine kinaseinhibitors);

(iii) antiproliferative/antineoplastic drugs and combinations thereof,as used in medical oncology, such as antimetabolites (for exampleantifolates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); antitumourantibiotics (for example anthracyclines like doxorubicin, daunomycin,epirubicin and idarubicin, mitomycin-C, dactinomycin, mithramycin);platinum derivatives (for example cisplatin, carboplatin); alkylatingagents (for example nitrogen mustard, melphalan, chlorambucil,busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa);antimitotic agents (for example vinca alkaloids like vincrisitine andtaxoids like taxol, taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan);

(iv) antiangiogenic agents that work by different mechanisms from thosedefined hereinbefore (for example receptor tyrosine kinases like Tie-2,inhibitors of integrin .alpha.v.beta.3 function, angiostatin, razoxin,thalidomide), and including vascular targeting agents; and

(v) differentiation agents (for example retinoic acid and vitamin D).

In methods using simultaneous administration, the agents can be presentin a combined composition or can be administered separately. Alsoprovided are pharmaceutical compositions comprising at least onecompound, or pharmaceutically acceptable salt thereof, described herein,and one or more anti-tumor agent as described herein. Similarly, alsoprovided are packaged pharmaceutical compositions containing apharmaceutical composition comprising at least one compound, orpharmaceutically acceptable salt thereof, described herein, and anothercomposition comprising one or more one or more anti-tumor agent asdescribed herein. When used in combination with one or more additionalpharmaceutical agent or agents, the described herein may be administeredprior to, concurrently with, or following administration of theadditional pharmaceutical agent or agents.

In some embodiments, the compounds, or pharmaceutically acceptable saltsthereof, described herein, are administered in conjunction with surgeryor radiotherapy, optionally in combination with one or more additionalagents used in the treatment of cancer.

The dosages of the compounds described herein depend upon a variety offactors including the particular syndrome to be treated, the severity ofthe symptoms, the route of administration, the frequency of the dosageinterval, the particular compound utilized, the efficacy, toxicologyprofile, pharmacokinetic profile of the compound, and the presence ofany deleterious side-effects, among other considerations.

The compound, or pharmaceutically acceptable salt thereof, describedherein is typically administered at dosage levels and in a mannercustomary for HDAC inhibitors. For example, the compound, orpharmaceutically acceptable salt thereof, can be administered, in singleor multiple doses, by oral administration at a dosage level of generally0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, such as 0.1-70mg/kg/day, for example, 0.5-10 mg/kg/day. Unit dosage forms can containgenerally 0.01-1000 mg of at least one compound, or pharmaceuticallyacceptable salt thereof, described herein, for example, 0.1-50 mg of atleast one compound, or pharmaceutically acceptable salt thereof,described herein. For intravenous administration, the compounds can beadministered, in single or multiple dosages, at a dosage level of, forexample, 0.001-50 mg/kg/day, such as 0.001-10 mg/kg/day, for example,0.01-1 mg/kg/day. Unit dosage forms can contain, for example, 0.1-10 mgof at least one compound, or pharmaceutically acceptable salt thereof,described herein.

A labeled form of a compound, or pharmaceutically acceptable saltthereof, described herein can be used as a diagnostic for identifyingand/or obtaining compounds that have the function of modulating anactivity of HDAC as described herein. The compound, or pharmaceuticallyacceptable salt thereof, described herein may additionally be used forvalidating, optimizing, and standardizing bioassays.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

In carrying out the procedures of the methods described herein, it is ofcourse to be understood that reference to particular buffers, media,reagents, cells, culture conditions and the like are not intended to belimiting, but are to be read so as to include all related materials thatone of ordinary skill in the art would recognize as being of interest orvalue in the particular context in which that discussion is presented.For example, it is often possible to substitute one buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to be able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

EXAMPLES

The compounds, or pharmaceutically acceptable salts thereof,compositions, and methods described herein are further illustrated bythe following non-limiting examples.

As used herein, the following abbreviations have the following meanings.If an abbreviation is not defined, it has its generally acceptedmeaning.

Abbreviations

aq. Aqueous

DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCM: Dichloromethane

DDQ: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

DME: Dimethoxyethane

DIPEA: Diisopropylethylamine

DMAP: Dimethylaminopyridine

DMF: Dimethylformamide

DMSO: Dimethylsulfoxide

ES+: Electrospray Positive Ionisation

ES−: Electrospray Negative Ionisation

Et₂O: Diethyl ether

EtOAc: Ethyl acetate

h: Hour(s)

HPLC: High Performance Liquid Chromatography

i-hex: iso-Hexane

IPA: iso-Propyl alcohol

LCMS: Liquid Chromatography Mass Spectrometry

LiHMDS: Lithium bis(trimethylsilyl)amide

M: Mass

MeCN: Acetonitrile

MeOH: Methanol

min: Minute(s)

MS: Mass spectrum

NBS: N-Bromosuccinimide

NMR: Nuclear Magnetic Resonance

RT: Retention time

r.t.: Room temperature

sat.: Saturated

SFC: Supercritical Fluid Chromatography

TBAF: Tetrabutylammonium fluoride

tBu: tert-Butyl

TFA: Trifluoroacetic acid

TFFH: Fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate

THF: Tetrahydrofuran

Compounds were named with the aid of the Cambridgesoft ChemistryCartridge (v. 9.0.0.182) software.

All reactions involving air- or moisture-sensitive reagents wereperformed under a nitrogen atmosphere using dried solvents andglassware.

Analytical Conditions

Analytical Method # Description Analytical method 1 Solvents:Acetonitrile (far UV grade) with 0.1% (v/v) formic acid. Water (highpurity via PureLab Option unit) with 0.1% formic acid Column: PhenomenexLuna 5 μm C18 (2), 100 × 4.6 mm (Plus guard cartridge) Flow Rate: 2mL/min gradient: A: Water/formic acid B: MeCN/formic acid Time A % B %0.00 95 5 3.50 5 95 5.50 5 95 5.60 95 5 6.50 95 5 Typical Injections 2-7μL (concentration~0.2- 1.0 mg/mL) Analytical method 2 Solvents:Acetonitrile (Far UV grade) with 0.1% (V/V) formic acid Water (Highpurity via PureLab Ultra unit) with 0.1% formic acid Column: Hichrom ACE3 C18-AR mixed mode column 100 × 4.6 mm Flow Rate: 1 mL/min gradient: A:Water/formic B: MeCN/formic Time A % B % 0.00 98 2 3.00 98 2 12.00 0 10015.4 0 100 15.5 98 2 17 98 2 Typical Injections 0.2-10 μL Analyticalmethod 3 Solvents: - Acetonitrile (Far UV grade) with 0.1% (V/V) formicacid Water (High purity via PureLab Ultra unit) with 0.1% formic acidColumn. Supelco, Ascentis ® Express C18 or Hichrom Halo C18, 2.7 μm C18,150 × 4.6 mm. Both latest technology fused core columns Flow Rate: 1ml/min Gradient: A: Water/formic B: MeCN/formic Time A % B % 0.00 96 43.00 96 4 9.00 0 100 13.6 0 100 13.7 96 4 15 96 4 Typical Injections0.2-10 ul

Preparation of Intermediates 1 and 2:(1S,4R)-4-(3-Fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one and(R)-methyl-1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate

Method 1

Step 1: (S)-1,4-Dibromobutan-2-ol

To a stirred solution of (S)-butane-1,2,4-triol (2 g, 18.9 mmol) andtriphenylphosphine (9.9 g, 37.7 mmol) in DCM (100 mL) at 0° C. was addedNBS (6.7 g, 37.7 mmol) portionwise. The mixture was allowed to warm tor.t. and stirred for 17 h. The reaction mixture was washed with water(2×100 mL) and sat. brine solution (100 mL) and the organics passedthrough a phase separator before concentrating in vacuo. The residue wasdissolved in DCM (10 mL) and added to rapidly stirred Et₂O (200 mL). Theresulting solid was removed by vacuum filtration. Additional solidprecipitated in the filtrate during filtration, so this process wasrepeated several times to remove residual triphenylphosphine oxide. Thefiltrate was concentrated and the resulting oil purified by flash silicacolumn chromatography (gradient elution 5% EtOAc in i-hex to 10% EtOAcin i-hex) to give the title compound as a colorless oil (1.5 g, 35%). ¹HNMR δ (ppm)(CHCl₃-d): 4.09-4.01 (1H, m), 3.61-3.50 (3H, m), 3.42 (1H,dd, J=10.4, 6.7 Hz), 2.18 (1H, dd, J=5.4, 0.8 Hz), 2.13-2.01 (2H, m).

Step 2: (S)-1,4-Dibromobutan-2-yl 2-(3-fluoro-2-methylphenyl)acetate

To a stirred solution of (S)-1,4-dibromobutan-2-ol (1.43 g, 6.16 mmol)in DCM (30 mL) was added 2-(3-fluoro-2-methylphenyl)acetic acid (941 mg,5.60 mmol), dicyclohexylcarbodiimide (1.27 g, 6.16 mmol) and DMAP (20mg, catalytic) and the mixture stirred at r.t. for 17 h. The reactionwas filtered and a white solid was removed by filtration and washed withDCM (3×25 mL). The filtrate was collected and washed with 1 M HCl_((aq))(30 mL), sat. brine solution (30 mL) and the organics passed through aphase separator and concentrated. Purification by flash silicachromatography (gradient elution i-hex to 20% EtOAc in i-hex) gave thetitle compound as a white crystalline solid (2.06 g, 96%). ¹H NMR δ(ppm)(CHCl₃-d): 7.15-7.07 (1H, m), 7.02-6.93 (2H, m), 5.20-5.12 (1H, m),3.70 (2H, s), 3.58 (1H, dd, J=11.1, 4.7 Hz), 3.45 (1H, dd, J=11.1, 4.3Hz), 3.34 (1H, ddd, J=10.3, 6.6, 5.5 Hz), 3.25 (1H, ddd, J=10.3, 8.4,6.1 Hz), 2.35-2.26 (1H, m), 2.24 (3H, d, J=2.7 Hz), 2.26-2.12 (1H, m).

Step 3:(1S,4R)-4-(3-Fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one(Intermediate 1)

To a stirred solution of (S)-1,4-dibromobutan-2-yl2-(3-fluoro-2-methylphenyl)acetate (2.05 g, 5.37 mmol) in 1,4-dioxane(50 mL) at r.t., was added LiHMDS (11.8 mL, 11.8 mmol, 1 M in THF) at arate of 1 mL/min. After complete addition, the mixture was stirred for 1h and quenched with 1 M aq. HCl (20 mL) and then extracted into EtOAc(3×50 mL). The combined organics were washed with water (50 mL) and sat.brine solution (50 mL), separated, dried (MgSO₄), filtered andconcentrated. Purification by flash silica chromatography (gradientelution i-hex to 5% EtOAc in i-hex) gave the title compound as a whitecrystalline solid (890 mg, 75%). MS (ES+) 221 (M+H)⁺; ¹H NMR δ(ppm)(CHCl₃-d): 7.17-7.08 (1H, m), 7.07-6.97 (2H, m), 5.00 (1H, d,J=2.10 Hz), 2.81 (1H, dd, J=10.4, 2.4 Hz), 2.40-2.18 (2H, m), 2.30 (3H,d, J=2.3 Hz), 2.13-2.07 (2H, m), 1.93 (1H, d, J=10.3 Hz).

Step 4:(1R,3S)-Methyl-1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate

To a stirred solution of(1R,4S)-4-(3-fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one (890mg, 4.05 mmol) in MeOH (30 mL) was added 4 M HCl in dioxane (1 mL). Themixture was heated to 60° C. for 17 h and then concentrated.Purification by flash silica chromatography (gradient elution i-hex to30% EtOAc in i-hex) gave the title compound as a white crystalline solid(766 mg, 75% [95% based on recovered starting material]). ¹H NMR δ(ppm)(CHCl₃-d): 7.18-7.06 (2H, m), 6.98-6.89 (1H, m), 4.42-4.37 (1H, m),3.66 (3H, s), 2.74-2.69 (1H, m), 2.66-2.58 (1H, m), 2.55 (1H, d, J=7.85Hz), 2.29-2.13 (3H, m), 2.13 (3H, d, J=2.7 Hz), 1.83-1.72 (1H, m).

Step 5:(R)-Methyl-1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate(Intermediate 2)

To a solution of(1S,3R)-methyl-1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate(766 mg, 3.04 mmol) in anhydrous DCM (20 mL) was added Dess-MartinPeriodinane (1.55 g, 3.64 mmol). The reaction mixture was stirred atr.t. for 4 h. Reaction mixture was quenched with a mixture of 10%Na₂S₂O₃ and sat. NaHCO₃ solution (1:1, 50 mL) and then rapidly stirredfor 30 min. Organic layers were extracted with further DCM (2×50 mL),then dried, filtered (phase separation cartridge) and concentrated togive a pale yellow oil. The residue was purified by flash silica columnchromatography (gradient elution i-hex to 20% EtOAc in i-hex) to givethe title compound as a colorless solid (656 mg, 86%). MS (ES+) 251(M+H)⁺; ¹H NMR δ (ppm)(CHCl₃-d): 7.28-7.19 (1H, m), 7.17-7.02 (2H, m),3.76 (3H, s), 3.23 (1H, d, J=17.9 Hz), 2.88-2.79 (1H, m), 2.69-2.33 (4H,m), 2.19 (3H, d, J=2.7 Hz). SFC (Analytical) (Chiralpak IA 5/95 IPA/CO₂,5.0 mL/min, 120 bar, 40° C.) RT 2.4 min; Chiral HPLC (Chiralpak IC 10/90IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0 mL/min) RT 10.35 min(95.7% ee). Double recrystallization from hot heptane gaveenantioenriched product (1.5 g, >99.5% ee).

Preparation of Intermediate 3: (S)-Methyl1-(3-fluoro-2-methylphenyl)-3-oxocyclopentane-carboxylate

Following Method 1 starting from (S)-butane-1,2,4-triol.

Method 2

Step 1: (S)-2-Hydroxybutane-1,4-diyl dimethanesulfonate

(S)-Butane-1,2,4-triol (20.0 g, 0.19 mol) was dissolved in anhydrouspyridine (85 mL). The reaction mixture was rapidly stirred whilst beingcooled to −10° C. (NaCl/ice bath). Methanesulfonyl chloride (44.3 g, 30mL, 0.40 mol) was then added drop-wise whilst maintaining internal flasktemperature at <4° C. (˜3 h). Once addition was complete the reactionmixture was stirred at r.t. for a further 1 h. After this time reactionwas cooled to 4° C. and 2 M aq. HCl (200 mL) was added over 20 min. Theresulting solution was partitioned with EtOAc (300 mL), washed withfurther 2 M aq. HCl (200 mL), dried, filtered (phase separationcartridge) and concentrated to give a yellow oil which partiallysolidified on standing. The residue was dissolved in the minimum hotEtOAc and left to stand at −20° C. for 16 h. Precipitated solids werefiltered and washed with cold Et₂O/i-hex (1:9, 50 mL) to give the titlecompound as colorless crystals (26.8 g, 55%). [Purification can also beachieved via flash silica column chromatography (Et₂O to EtOAc)—thisgives a close running impurity which can be easily separated at the nextstep.] R_(f)=0.2 (66% EtOAc/i-hex); MS (ES+) 263 (M+H)⁺; ¹H NMR δ (ppm):(DMSO-d₆): 5.33 (1H, s), 4.35-4.23 (2H, m), 4.19-3.99 (2H, m), 3.89-3.81(1H, m), 3.19 (3H, s), 3.18 (3H, s), 1.94-1.84 (1H, m), 1.77-1.66 (1H,m).

Step 2:(S)-2-((tert-Butyldiphenylsilyl)oxy)butane-1,4-diyldimethanesulfonate

To a 4° C. solution of (S)-2-hydroxybutane-1,4-diyl dimethanesulfonate(23.2 g, 0.09 mol) in anhydrous DMF (75 mL) was addedtert-butylchlorodiphenylsilane (36.5 g, 34.5 mL, 0.11 mol) followed byimidazole (10.0 g, 0.15 mol). The reaction mixture was stirred at 4° C.for 1 h then at r.t. for a further 16 h. The reaction mixture wasquenched using ice water (200 mL) with rapid stirring for 30 min. Thecorresponding solution was partitioned with EtOAc (300 mL), washed withwater (2×200 mL), and then sat. NaCl solution (250 mL). The combinedorganic layers were dried, filtered (phase separation cartridge) andconcentrated to give a yellow oil. Purification by flash silica columnchromatography (gradient elution i-hex to 50% EtOAc in i-hex) gave thetitle compound as a colorless glass (42.0 g, 93%). R_(f)=0.55 (66%EtOAc/i-hex); MS (ES+) 501 (M+H)⁺; ¹H NMR δ (ppm)(DMSO-d₆): 7.67-7.63(4H, m), 7.52-7.41 (6H, m), 4.31-4.16 (2H, m), 4.13-4.01 (3H, m), 3.08(3H, s), 3.02 (3H, s), 1.92 (2H, dd, J=12.2, 6.1 Hz), 1.02 (9H, s).

Step 3: (S)-tert-Butyl((1,4-dibromobutan-2-yl)oxy)diphenylsilane

To a solution of (S)-2-((tert-butyldiphenylsilyl)oxy)butane-1,4-diyldimethanesulfonate (42.0 g, 0.08 mol) in anhydrous DMF (320 mL) wasadded lithium bromide (22.0 g, 0.25 mol). The reaction mixture wasstirred at 105° C. for 1.5 h. The reaction mixture was cooled to r.t.and partitioned between EtOAc (500 mL) and water (300 mL). Organiclayers were washed with further water (2×300 mL) and sat. NaCl solution(400 mL). The combined organic layers were dried, filtered (phaseseparation cartridge) and concentrated to give a yellow oil.Purification by flash silica column chromatography (gradient elutioni-hex to 10% EtOAc in i-hex) gave the title compound as a colorless oilwhich darkens upon standing (30.0 g, 80%). R_(f)=0.80 (60% EtOAc/i-hex);MS (ES+) 471 (M+H)⁺; ¹H NMR δ (ppm)(DMSO-d₆): 7.69-7.63 (4H, m),7.52-7.41 (6H, m), 4.07-3.99 (1H, m), 3.53-3.40 (4H, m), 2.10 (2H, dd,J=13.0, 6.5 Hz), 1.04 (9H, s).

Step 4: (1S,3S)-Methyl1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate

To a solution of(S)-tert-butyl((1,4-dibromobutan-2-yl)oxy)diphenylsilane (6.43 g, 0.014mol) and methyl 2-(3-fluoro-2-methylphenyl)acetate (2.0 g, 0.011 mol) inanhydrous DMF (80 mL) was added 18-crown-6 (0.2 g, catalytic). Thereaction mixture was stirred at r.t. for 10 min then sodium hydride (60%dispersion in mineral oil 1.05 g, 0.03 mol) was added portion-wise over1.5 h. Reaction mixture was stirred at r.t. for a further 16 h. Thereaction mixture was cooled to 4° C. and quenched by drop-wise additionof 5% NaH₂PO₄ solution (15 mL). The solution was then partitionedbetween EtOAc (250 mL) and water (200 mL). The organic layer was washedwith further water (2×150 mL), sat. NaCl solution (200 mL), then dried,filtered (phase separation cartridge) and concentrated to give a yellowoil. The resultant oil was dissolved in anhydrous THF (80 mL) and TBAF(1M in THF, 0.03 mol, 30 mL) was added. Reaction mixture was thenstirred at r.t. for 3 h. After this time the reaction mixture wasconcentrated under reduced pressure and purified by flash silica columnchromatography (gradient elution i-hex to 33% EtOAc in i-hex) to givethe title compound as a colorless oil (2.10 g, 78%, 5:1 mixture ofisomers). R_(f)=0.1 (20% EtOAc/i-hex); MS (ES+) 253 (M+H)⁺.

Step 5:(1S,4R)-4-(3-Fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one

To a solution of (1S,3S)-methyl1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (5:1 (1S,3S):(1R:3S) mixture of isomers, 2.10 g, 0.0086 mol) in anhydrousacetonitrile (100 mL) was added DBU (1.44 g, 1.42 mL, 0.0095 mol). Thereaction mixture was stirred at 80° C. for 20 h. The reaction mixturewas cooled to r.t. and partitioned between DCM (125 mL) and 1 M HCl (100mL). Organic layers were extracted, washed with water (100 mL), thendried, filtered (phase separation cartridge) and concentrated to give ayellow oil. The residue was purified by flash silica columnchromatography (gradient elution i-hex to 40% EtOAc in i-hex) to givethe title compound(1S,4R)-4-(3-fluoro-2-methylphenyl)-2-oxabicyclo[2.2.1]heptan-3-one as acolorless oil (256 mg); R_(f)=0.3 (33% EtOAc/i-hex); MS (ES+) 221(M+H)⁺; ¹H NMR δ (ppm)(CHCl₃-d): 7.18-7.10 (1H, m), 7.09-6.98 (2H, m),5.00 (1H, d, J=2.1 Hz), 2.81 (1H, dd, J=10.4, 2.4 Hz), 2.39-2.32 (1H,m), 2.32 (3H, d, J=2.8 Hz), 2.30-2.21 (1H, m), 2.15-2.07 (2H, m), 1.93(1H, d, J=10.3 Hz); ¹⁹F NMR: −114.43; and unreacted starting material(1S,3S)-methyl1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylateas acolorless oil (1.63 g); R_(f)=0.15 (33% EtOAc/i-hex); MS (ES+)consistent with target (M+H)⁺; ¹H NMR δ (ppm)(CHCl₃-d): 7.24 (1H, d,J=8.03 Hz), 7.19-7.11 (1H, m), 6.97-6.90 (1H, m), 4.56-4.49 (1H, m),3.62 (3H, s), 3.07 (1H, dd, J=13.8, 6.6 Hz), 2.47-2.42 (2H, m), 2.11(3H, d, J=2.8 Hz), 2.10-2.01 (1H, m), 1.92 (1H, ddd, J=13.9, 4.5, 1.1Hz), 1.79-1.70 (1H, m), 1.38 (1H, d, J=4.2 Hz); ¹⁹F NMR: −114.83.

Step 6: (S)-Methyl1-(3-fluoro-2-methylphenyl)-3-oxocyclopentanecarboxylate (Intermediate3)

To a solution of (1S,3S)-methyl1-(3-fluoro-2-methylphenyl)-3-hydroxycyclopentanecarboxylate (1.60 g,6.5 mmol) in anhydrous DCM (100 mL) was added Dess-Martin Periodinane(3.32 g, 7.8 mmol). The reaction mixture was stirred at r.t. for 4 h.Reaction mixture was quenched with a mixture of 10% Na₂S₂O₃ and sat.NaHCO₃ solution (1:1, 100 mL) and then rapidly stirred for 30 min.Organic layers were extracted with further DCM (2×50 mL), then dried,filtered (phase separation cartridge) and concentrated to give a paleyellow oil. The residue was purified by flash silica columnchromatography (gradient elution i-hex to 20% EtOAc in i-hex) to givethe title compound as a colorless solid (1.42 g, 84%). R_(f)=0.25 (33%EtOAc/i-hex); ¹H NMR δ (ppm)(CHCl₃-d): 7.28-7.19 (1H, m), 7.17-7.02 (2H,m), 3.76 (3H, s), 3.28 (1H, d, J=17.9 Hz), 2.88-2.79 (1H, m), 2.69-2.33(4H, m), 2.19 (3H, d, J=2.7 Hz); SFC (Analytical) (Chiralpak IA 5/95IPA/CO₂, 50 mL/min, 120 bar, 40° C.) RT 2.1 min (>99.5% ee); Chiral HPLC(Chiralpak IC 10/90 IPA/MeOH (50/50/0.1% formic acid)/heptane, 1.0mL/min) RT 9.48 min.

Preparation of Intermediates 4-8: 3-tert-butyl 1-methyl3′-fluoro-4-hydroxy-2′-methyl-1,2,5,6-tetrahydro-[1,1′-biphenyl]-1,3-dicarboxylate,methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate, methyl1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclohexanecarboxylate, methyl2-amino-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylateand methyl2-bromo-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

Step 1: 3-tert-Butyl 1-methyl3′-fluoro-4-hydroxy-2′-methyl-1,2,5,6-tetrahydro-[1,1′-biphenyl]-1,3-dicarboxylate(Intermediate 4)

Methyl 2-(3-fluoro-2-methylphenyl)acetate (3.13 g, 17.2 mmol), DMF (30mL) and t-butyl acrylate (5.22 mL, 36.12 mmol) were combined at roomtemperature under a nitrogen atmosphere. Reaction mixture was cooledwith an ice bath and NaH (60% in oil) (3.44 g, 86 mmol) was addedportionwise. Reaction mixture was stirred at room temperature for 20 hand then carefully quenched with sat. aq. NH₄Cl solution, with ice bathcooling. The reaction mixture was extracted with EtOAc which was thenwashed with water, brine and evaporated to dryness onto silica, thenpurified by flash chromatography to give 3-tert-butyl 1-methyl3′-fluoro-4-hydroxy-2′-methyl-1,2,5,6-tetrahydro-[1,1′-biphenyl]-1,3-dicarboxylateas a white solid (2.14 g, 34%). ¹H NMR δ (ppm)(CHCl₃-d): 7.20-7.05 (1H,m), 7.00-6.85 (2H, m), 3.70 (3H, s), 2.75 (2H, m), 2.4-2.15 (3H, m),2.13 (3H, d, J=2.4 Hz), 1.85-1.70 (1H, m), 1.55 (9H, s). OH resonancenot observed.

Step 2: Methyl 1-(3-fluoro-2-methylphenyl)-4-oxocyclohexanecarboxylate(Intermediate 5)

Intermediate 4 (2.14 g, 5.88 mmol) and TFA (10 mL) were combined andstirred at room temperature for 20 h. The TFA was then removed byevaporation in vacuo and the residue was azeotroped with toluene.Toluene (100 mL), MeOH (10 mL) and NaHCO₃ (200 mg) were added and themixture was heated to 105° C. for 20 h. The reaction mixture was thenevaporated to dryness onto silica and purified by flash chromatographyto give the title compound as a white solid (799 mg, 52%). LCMS (ES+)265 (M+H)⁺; ¹H NMR δ (ppm)(CHCl₃-d): 7.22-7.15 (2H, m), 7.05-6.95 (1H,m), 3.72 (3H, s), 2.77-2.64 (4H, m), 2.46-2.41 (2H, m), 2.27-2.20 (2H,m), 2.21 (3H, d, J=2.4 Hz).

Step 3: Methyl1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclohexanecarboxylate(Intermediate 6)

tBuOK (233 mg, 2.08 mmol) and THF were combined under a nitrogenatmosphere. The reaction mixture was cooled with an ice bath and ethylformate (0.61 mL, 7.56 mmol) was added dropwise—care: effervescence.After 20 min intermediate 5 (500 mg, 1.89 mmol) was added dropwise as asolution in ethyl formate (2.5 mL). The reaction mixture was stirred fora further 1 h with ice bath cooling then diluted with EtOAc and washedwith 1 N HCl, dried (MgSO₄) and evaporated to dryness to give the titlecompound as a brown gum (516 mg, 94%). LCMS (ES−) 291 (M−H)⁻.

Step 4: Methyl2-amino-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate(Intermediate 7)

Intermediate 5 (550 mg, 2.08 mmol), thiourea (228 mg, 3 mmol) and AcOH(10 mL) were combined in a sealed tube. Bromine (0.107 mL, 2.08 mmol)was added and the mixture was heated to 65° C. for 18 h. Reactionmixture was cooled and evaporated to dryness. Residue was partitionedbetween 2 N NaOH soln. and EtOAc. Extracted with EtOAc (2×), organicswere then dried (MgSO₄) and evaporated to dryness to give the titlecompound as a tan solid (641 mg, 96%). LCMS (ES+) 321 (M+H)⁺.

Step 5: Methyl2-bromo-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate(Intermediate 8)

Intermediate 7 (1.94 g, 6.06 mmol), CuBr₂ (1.49 g, 6.67 mmol) and MeCN(100 mL) were combined. t-Butyl nitrite (0.94 mL, 7.88 mmol) was addeddropwise—care: exotherm. After stirring for 2 h the reaction mixture wasquenched with 1N HCl and extracted with EtOAc (2×), dried (MgSO₄) andevaporated to dryness to give the title compound as a brown solid (2.08g, 89%). LCMS (ES+) 384/386 (M+H)⁺.

Step 6: 4-Ethyl 1-methyl1-(3-fluoro-2-methylphenyl)-5-oxocycloheptane-1,4-dicarboxylate(Intermediate 9)

Intermediate 5 (1.0 g, 3.79 mmol) was dissolved in dry DCM (11 mL) andcooled to 0° C. under a nitrogen atmosphere. Triethyloxoniumtetrafluoroborate (4.6 mL, 4.55 mmol, 1.0 M in DCM) was added in oneportion. Ethyl diazoacetate (0.48 mL, 4.55 mmol) was added dropwise over10 min maintaining the internal temperature at 0° C. The reaction wasstirred at 0° C. for 3 h then quenched with saturated sodium bicarbonatesolution. The reaction mixture was transferred to a separating funneland extracted with DCM (×2). The combined organic extracts were washedwith water, dried (magnesium sulfate), filtered and evaporated todryness to afford the title compound as a yellow oil (1.47 g, >100%).NMR indicated a mixture of enol and ketone forms. Used without furtherpurification in the next step.

Preparation of Intermediate 10: (S)-Methyl2-bromo-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

Step 1: (S)-Methyl2-amino-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

Intermediate 3 (0.75 g, 3.0 mmol), thiourea (0.25 g, 3.3 mmol) andbromine (0.52 g, 3.3 mmol) were added to acetic acid (10 mL) and heatedto 100° C. for 16.5 h. The reaction was cooled, diluted with EtOAc (50mL) and washed with NaOH (2N, 2×50 mL), water then brine followed byconcentration under vacuum to give the title compound (0.66 g) which wasused in the next step without further purification. LCMS (ES+) 307(M+H)⁺.

Step 2: (S)-Methyl2-bromo-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

To a solution of (S)-methyl2-amino-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate(0.54 g, 1.79 mmol) and copper (II) bromide (0.44 g, 1.96 mmol) in MeCN(10 mL) was added tert-butyl nitrite, drop-wise and the reaction mixturestirred at 20° C. for 0.6 h. The reaction was quenched on HCl (1 N, 50mL), extracted into DCM (75 mL) and subjected to an aqueous workup.Separation of the organic and concentration under vacuum gave crude thetitle compound (0.63 g) which was used in the next step without furtherpurification. LCMS (ES+) 370/372 (M+H)⁺.

Preparation of Intermediates 11 and 12: Methyl3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate andmethyl2-bromo-5-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

Step 1: Methyl 2-allyl-2-(3-fluoro-2-methylphenyl)pent-4-enoate

A solution of methyl 2-(3-fluoro-2-methylphenyl)acetate (1.95 g, 10.7mmol) and allyl bromide (0.96 mL, 10.7 mmol) in dry DMF (20 mL) wastreated at r.t under N₂ with NaH (60 wt % in oil, 448 mg, 10.7 mmol) andstirred for 2 h. After this time a further equivalent of allyl bromideand NaH were added, followed by a final addition of 0.5 equivalents ofallyl bromide and NaH 1 h later. 1 h after the final addition thereaction was quenched with H₂O (1 mL), diluted with EtOAc (100 mL) andwashed with water (4×20 mL) and brine (20 mL). The organic layer wasdried (Na₂SO₄) and concentrated to give 2.96 g yellow liquid that wasused without further purification.

Step 2: Methyl 1-(3-fluoro-2-methylphenyl)cyclopent-3-enecarboxylate

A solution of methyl 2-allyl-2-(3-fluoro-2-methylphenyl)pent-4-enoate(2.96 g from previous step, ˜10.7 mmol) and Grubbs 2^(nd) generationcatalyst (210 mg, 0.25 mmol) in DCM (300 mL) was stirred under N₂ at r.tfor 24 h. The mixture was concentrated onto silica and purified by flashsilica chromatography (gradient elution, 0-50% EtOAc in i-hex) to givethe title compound (1.85 g) as a pale brown liquid of approximately 80%purity.

Step 3: Methyl3-bromo-1-(3-fluoro-2-methylphenyl)-4-hydroxycyclopentanecarboxylate

A solution of methyl1-(3-fluoro-2-methylphenyl)cyclopent-3-enecarboxylate (1.66 g, 7.09mmol), NBS (1.39 g, 7.81 mmol) and ammonium acetate (80.3 mg, 1.04 mmol)in acetone (25 mL) and water (6 mL) was stirred at r.t for 2 h. Afterevaporating solvents the mixture was partitioned between water (20 mL)and DCM (40 mL) and the organic layer concentrated. The residue waspurified by flash silica chromatography (gradient elution of 0% to 100%EtOAc in i-hex) to give the title compound as a colorless liquid (1.74g, 5.25 mmol, 74%) as a mixture of stereoisomers.

Step 4: Methyl3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate(Intermediate 11)

A suspension of methyl3-bromo-1-(3-fluoro-2-methylphenyl)-4-hydroxycyclopentanecarboxylate(1.74 g, 5.25 mmol) and Dess-Martin periodinane (2.44 g, 5.75 mmol) inDCM (50 mL) was stirred at r.t for 16 h. The reaction mixture wasconcentrated onto silica and purified by flash silica chromatography(gradient elution of 0% to 100% EtOAc in i-hex) to give the titlecompound as a colorless liquid (1.58 g, 4.80 mmol, 91%) as a mixture ofstereoisomers.

Step 5: Methyl1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate

A solution of intermediate 11 (800 mg, 2.43 mmol) and potassiumthiocyanate (500 mg, 5.15 mmol) in dry acetonitrile (8 mL) was heated at100° C. under microwave irradiation for 10 min. After cooling to r.t.the mixture was combined with two other identical reactions andpartitioned between water (20 mL) and DCM (60 mL), dried (phaseseparator) and concentrated. Purification by flash silica chromatography(gradient elution, 0-100% EtOAc in i-hex) gave the title compound (2.07g, 6.74 mmol, 93%) as white prisms in a 2:1 diastereomeric mixture.

Step 6: Methyl2-bromo-5-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate(Intermediate 12)

A solution of methyl1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate(338 mg, 1.10 mmol) in HBr (33 wt % in AcOH, 1 mL) and AcOH (3 mL) washeated at 100° C. under microwave irradiation for 10 min. After coolingto rt, the mixture was combined with three other identical reactions andpoured into water (30 mL). DCM (50 mL) was added and the mixture wasstirred vigorously at r.t for 5 min. The DCM layer was washed with sat.aq. NaHCO₃ (40 mL), dried (phase separator) and concentrated.Purification by flash silica chromatography (gradient elution, 0-50%EtOAc in i-hex) gave the title compound (620 mg, 1.67 mmol, 51%) as acolorless liquid.

Preparation of Intermediates 13-16: (1R)-Methyl3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate

Step 1: (1R)-Methyl3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate(Intermediate 13)

To a cooled solution of Intermediate 2 (4.5 g, 18 mmol) in DCM (100 mL)at −78° C. was added 4 M HCl in dioxane (0.45 mL). This was stirred for5 min before dropwise addition of bromine (2.88 g, 18 mmol). Thereaction was stirred at −78° C. for 1 h then removed from the ice-bath.After an additional 1 h at r.t the reaction was diluted with water (100mL) and the organics collected. The aqueous portion was re-extractedwith DCM (100 mL), and the combined organics passed through a phaseseparator and concentrated. Purification by flash chromatography (10%EtOAc in i-hex) gave the title compound as a colorless oil whichcrystallized on standing (2.37 g, 40%). LCMS (ES+) 329/331 (M+H)⁺.

Step 2: (S)-Methyl1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate

A solution of Intermediate 13 (800 mg, 2.43 mmol) and potassiumthiocyanate (500 mg, 5.15 mmol) in dry acetonitrile (8 mL) was heated at100° C. under microwave irradiation for 10 min. After cooling to r.t.the mixture was combined with two other identical reactions andpartitioned between water (20 mL) and DCM (60 mL), dried (phaseseparator) and concentrated. Purification by flash silica chromatography(gradient elution, 0-100% EtOAc in i-hex) gave the title compound (2.07g, 6.74 mmol, 93%) as white prisms in a 2:1 diastereomeric mixture. LCMS(ES+) 308 (M+H)⁺.

Step 3: (S)-Methyl2-bromo-5-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate(Intermediate 14)

A solution of (S)-methyl1-(3-fluoro-2-methylphenyl)-3-oxo-4-thiocyanatocyclopentanecarboxylate(338 mg, 1.10 mmol) in HBr (33 wt % in AcOH, 1 mL) and AcOH (3 mL) washeated at 100° C. under microwave irradiation for 10 min. After coolingto r.t. the mixture was combined with three other identical reactionsand poured into water (30 mL). DCM (50 mL) was added and the mixture wasstirred vigorously at r.t. for 5 min. The DCM layer was washed with sat.aq. NaHCO₃ (40 mL), dried (phase separator) and concentrated.Purification by flash silica chromatography (gradient elution, 0-50%EtOAc in i-hex) gave the title compound (620 mg, 1.67 mmol, 51%) as acolorless liquid.

Steps 1-3 can be performed starting from Intermediate 3 to accessIntermediate 15 and Intermediate 16.

PREPARATION OF EXAMPLES Example 1:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Step 1: (1S)-Methyl1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclopentanecarboxylate

tBuOK (247 mg, 2.2 mmol) and THF (15 mL) were combined under a nitrogenatmosphere. The reaction mixture was cooled with an ice bath and ethylformate (0.64 mL, 8 mmol) was added dropwise—care effervescence. After15 min, Intermediate 3 (500 mg, 2 mmol) was added dropwise as a solutionin ethyl formate (2.5 mL). The reaction mixture was stirred for afurther 1 h with ice bath cooling then diluted with EtOAc and washedwith 1N HCl, dried (MgSO₄) and evaporated to dryness to give the titlecompound as a tan oil (569 mg, 100%). LCMS (ES+) 279 (M+H)⁺.

Step 2: (S)-Methyl5-(3-fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate

(1S)-Methyl1-(3-fluoro-2-methylphenyl)-3-formyl-4-oxocyclopentanecarboxylate (569mg, 2 mmol), acetic acid (10 mL) and phenylhydrazine (0.2 mL, 2 mmol)were combined in a sealed tube and heated to 70° C. for 1 h. Reactionmixture was then evaporated to dryness onto silica and purified by flashchromatography to give the title compound as a brown gum (451 mg, 64%).LCMS (ES+) 351 (M+H)⁺.

Step 3:(S)-5-(3-Fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylicacid

(S)-Methyl5-(3-fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate(451 mg, 1.29 mmol), MeOH (15 mL) and 15% aq. NaOH soln. (4 mL) werecombined in a sealed tube and heated to 70° C. for 1 day. Reactionmixture was evaporated to dryness, diluted with EtOAc, washed with 1NHCl and evaporated to dryness once more to give the title compound as abrown gum (315 mg, 73%). LCMS (ES+) 337 (M+H)⁺.

Step 4:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

(S)-5-(3-Fluoro-2-methylphenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylicacid (315 mg, 0.94 mmol), TFFH (264 mg, 1 mmol), DMF (2 mL) andtriethylamine (0.5 mL) were combined and stirred at room temperature for1.5 h. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (234 mg, 2 mmol) wasthen added and stirring continued for 1 day. Volatile solvents wereremoved in vacuo. MeOH (5 mL) and 2N HCl in Et₂O (2 mL) were added andreaction mixture was stirred for 2 h. Volatile solvents were removed invacuo and remaining crude material was purified by preparative HPLC togive the title compound as an off white solid (256 mg). LCMS (ES+) 352(M+H)⁺, RT 3.52 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.26 (1H, s), 8.80 (1H, br s), 7.70-7.60 (2H, m), 7.55-7.45 (3H, m),7.30 (1H, m), 7.25-7.00 (3H, m), 4.12 (1H, d), 3.40 (1H, d), 3.25 (1H,d), 3.20 (1H, d), 2.20 (3H, d, J=2.4 Hz).

Example 2:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a tan solid (64 mg). LCMS (ES+) 366 (M+H)⁺,RT 9.93 min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.23 (1H,s), 8.79 (1H, br s), 7.45-7.00 (8H, m), 3.76 (1H, d, 16 Hz), 3.45 (1H,d, J=15 Hz), 3.25 (1H, d, J=15 Hz), 2.51 (1H, d, J=16 Hz), 2.11 (3H, d,J=2.4 Hz), 2.01 (3H, s).

Example 3:(S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a white solid (115 mg). LCMS (ES+) 370(M+H)⁺, RT 3.43 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.22 (1H, s), 8.81 (1H, s), 7.70-7.30 (5H, m), 7.25-6.95 (3H, m), 3.83(1H, d, J=16 Hz), 3.45 (1H, d, J=15 Hz), 3.13 (1H, d, J=15 Hz), 3.03(1H, d, J=16 Hz), 2.12 (3H, d, J=2.8 Hz).

Example 4:(S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a white solid (85 mg). LCMS (ES+) 386/388(M+H)⁺, RT 3.78 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.27 (1H, s), 8.85 (1H, s), 7.75-7.45 (5H, m), 7.25-7.00 (3H, m), 4.11(1H, d, J=16 Hz), 3.41 (1H, d, J=16 Hz), 3.33 (1H, d, J=16 Hz), 3.15(1H, d, J=16 Hz), 2.17 (3H, d, J=2.4 Hz).

Example 5:(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off white solid (41 mg). LCMS (ES+) 370(M+H)⁺, RT 3.65 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.24 (1H, s), 8.81 (1H, s), 810 (1H, s), 7.78-7.74 (2H, m), 7.35-7.25(2H, m) 7.25-7.00 (3H, m), 3.65 (1H, d, J=16 Hz), 3.50 (1H, d, J=16 Hz),3.10 (1H, d, J=16 Hz), 3.05 (1H, d, J=16 Hz), 2.17 (3H, d, J=2.4 Hz).

Example 6:(S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a tan solid (129 mg). LCMS (ES+) 370 (M+H)⁺,RT 3.67 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.26 (1H,s), 8.83 (1H, br s), 7.60-7.45 (4H, m), 7.25-7.00 (4H, m), 4.13 (1H, d,J=16 Hz), 3.39 (1H, d, J=16 Hz), 3.31 (1H, d, J=16 Hz), 3.17 (1H, d,J=16 Hz), 2.18 (3H, d, J=2.4 Hz).

Example 7:(S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off white solid (108 mg). LCMS (ES+)386/388 (M+H)⁺, RT 3.37 min (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 10.22 (1H, s), 8.80 (1H, br s), 7.75-7.45 (5H, m),7.25-7.00 (3H, m), 3.7 (1H, d, J=16 Hz), 3.45 (1H, d, J=16 Hz), 3.5 (1H,d, J=15 Hz), 2.89 (1H, d, J=16 Hz), 2.11 (3H, d, J=2.8 Hz).

Example 8:(S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off white solid (15 mg). LCMS (ES+)386/388 (M+H)⁺, RT 3.52 min (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 10.24 (1H, s), 8.81 (1H, s), 8.15 (1H, s), 7.80-7.70(2H, m), 7.60-7.50 (2H, m), 7.25-7.00 (3H, m), 3.65 (1H, d, J=16 Hz),3.50 (1H, d, J=16 Hz), 3.11 (1H, d, J=16 Hz), 3.06 (1H, d, J=16 Hz), 2.1(3H, d, J=2.8 Hz).

Example 9:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a brown solid (60 mg). LCMS (ES+) 366 (M+H)⁺,RT 9.08 min (Analytical method 3); ¹H NMR δ (ppm)(DMSO-d₆): 10.26 (1H,s), 8.80 (1H, br s), 7.52 (2H, d, J=8.4 Hz), 7.43 (1H, s), 7.28 (2H, d,J=8 Hz), 7.25-7.20 (3H, m), 4.10 (1H, d, J=16 Hz), 3.40 (1H, d, J=16Hz), 3.22 (1H, d, J=16 Hz), 3.15 (1H, d, J=16 Hz), 2.32 (3H, s), 2.17(3H, d, J=2.8 Hz).

Example 10:(S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as tan solid (124 mg). LCMS (ES+) 404/406(M+H)⁺, RT 9.05 min (Analytical method 3); ¹H NMR δ (ppm)(DMSO-d₆):10.23 (1H, s), 8.80 (1H, br s), 7.70-7.60 (2H, m), 7.56 (1H, s),7.40-7.30 (1H, m), 7.25-7.00 (3H, m), 3.84 (1H, d, J=15 Hz), 3.40 (1H,d, J=15 Hz), 3.15 (1H, d, J=15 Hz), 3.00 (1H, d, J=15 Hz), 2.12 (3H, d,J=2.8 Hz).

Example 11:(S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as beige solid (131 mg). LCMS (ES+) 388 (M+H)⁺,RT 8.52 min (Analytical method 3); ¹H NMR δ (ppm)(DMSO-d₆): 10.21 (1H,s), 8.81 (1H, br s), 7.65-7.50 (2H, m), 7.45-7.30 (2H, m), 7.25-6.95(3H, m), 3.73 (1H, d, J=16 Hz), 3.53 (1H, d, J=16 Hz), 3.15 (1H, d, J=16Hz), 2.90 (1H, d, J=16 Hz), 2.10 (3H, d, J=2.8 Hz).

Example 12:(S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as grey solid (108 mg). LCMS (ES+) 380 (M+H)⁺,RT 9.03 min (Analytical method 3); ¹H NMR δ (ppm)(DMSO-d₆): 10.22 (1H,s), 8.80 (1H, br s), 7.39 (1H, s), 7.30-7.00 (6H, m), 3.76 (1H, d, J=16Hz), 3.44 (1H, d, J=16 Hz), 3.17 (1H, d, J=16 Hz), 2.79 (1H, d, J=16Hz), 2.33 (3H, s), 2.10 (3H, d, J=2.8 Hz), 2.00 (3H, s).

Example 13:(S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a tan solid (80 mg). LCMS (ES+) 380 (M+H)⁺,RT 3.50 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.23 (1H,s), 8.80 (1H, br s), 7.43 (1H, s), 7.30-7.00 (5H, m), 3.66 (1H, d,J=15.6 Hz), 3.39 (1H, d, J=15.2 Hz), 3.27 (1H, d, J=15.2 Hz), 2.54 (1H,d, J=15.6 Hz), 2.08 (3H, d, J=32.4 Hz), 2.01 (3H, s), 1.63 (1H, s).

Example 14:(S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a tan solid (146 mg). LCMS (ES+) 404/406(M+H)⁺, RT 9.86 min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆):10.22 (1H, s), 8.80 (1H, br s), 7.65-7.40 (4H, m), 7.25-7.00 (3H, m),3.69 (1H, d, J=16 Hz), 3.43 (1H, d, J=15.2 Hz), 3.17 (1H, d, J=15.2 Hz),2.80 (1H, d, J=16 Hz), 2.09 (3H, d, J=3.6 Hz).

Example 15:(S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a tan solid (157 mg). LCMS (ES+) 384 (M+H)⁺,RT 10.13 min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.22 (1H,s), 8.81 (1H, br s), 7.50-7.00 (7H, m), 3.81 (1H, d, J=16 Hz), 3.46 (1H,d, J=14.8 Hz), 3.12 (1H, d, J=15.2 Hz), 3.02 (1H, d, J=16 Hz), 2.32 (3H,d, J=2 Hz), 2.12 (3H, d, J=2.4 Hz).

Example 16:(S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2-yl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off white solid (126 mg). LCMS (ES+) 371(M+H)⁺, RT 3.55 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.24 (1H, s), 8.80 (1H, br s), 8.46 (1H, s), 8.00-7.85 (2H, m), 7.52(1H, s), 7.20-7.00 (3H, m), 4.03 (1H, d, J=16.8 Hz), 3.45 (1H, d, J=16.8Hz), 3.42 (1H, d, J=15.6 Hz), 3.06 (1H, d, J=15.2 Hz), 2.15 (3H, d,J=2.8 Hz).

Example 17:(S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off white solid (118 mg). LCMS (ES+) 388(M+H)⁺, RT 9.99 min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆):10.22 (1H, s), 8.80 (1H, br s), 7.70-7.60 (1H, m), 7.60-7.50 (2H, m),7.30-7.00 (4H, m), 3.82 (1H, d, J=15 Hz), 3.45 (1H, d, J=15 Hz), 3.14(1H, d, J=15 Hz), 3.01 (1H, d, J=16 Hz), 2.12 (3H, d, J=2.8 Hz).

Example 18:(S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off white solid (41 mg). LCMS (ES+) 344(M+H)⁺, RT 3.31 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.18 (1H, s), 8.80 (1H, br s), 7.20-7.00 (4H, m), 4.60-4.50 (1H, m),3.74 (1H, d, J=16 Hz), 3.37 (1H, d, J=16 Hz), 3.02 (1H, d, J=16 Hz),2.98 (1H, d, J=16 Hz), 2.15 (3H, d, J=2.8 Hz), 2.10-1.90 (2H, m),1.90-1.65 (4H, m), 1.65-1.52 (2H, m).

Example 19:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(pyrazin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as a brown solid (43 mg). LCMS (ES+) 354 (M+H)⁺,RT 3.09 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.25 (1H,s), 9.15 (1H, s), 8.82 (1H, br s), 8.56 (1H, d, J=2.8 Hz), 8.52 (1H, m),7.64 (1H, s), 7.20-7.00 (3H, m), 4.06 (1H, d, J=16.8 Hz), 3.46 (1H, d,J=17.2 Hz), 3.43 (1H, d, J=15.2 Hz), 3.09 (1H, d, J=15.2 Hz), 2.18 (3H,d, J=2.8 Hz).

Examples 20 and 21:(S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideand(S)-2-(4-(difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Two regioisomersobserved. Preparative HPLC gave(S)-2-(4-(difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off white solid (21 mg); LCMS (ES+) 418 (M+H)⁺, RT 3.7 min(Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.25 (1H, s), 8.82 (1H,s), 8.13 (1H, s), 7.78 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=9.2 Hz), 7.25(1H, t, J=74 Hz), 7.20-7.05 (2H, m), 3.66 (1H, d, J=16 Hz), 3.52 (1H, d,J=16 Hz), 3.11 (1H, d, J=16 Hz), 3.06 (1H, d, J=16 Hz), 2.18 (3H, d,J=2.4 Hz) and also(S)-1-(4-(difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off white solid (38 mg); LCMS (ES+) 418 (M+H)⁺, RT 10.55 min(Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.27 (1H, s), 8.82 (1H,br s), 7.69 (2H, d, J=10 Hz), 7.46 (1H, s), 7.29 (2H, d, J=10 Hz), 7.26(1H, t, J=74 Hz), 7.20-7.00 (2H, m), 4.12 (1H, d, J=16 Hz), 3.38 (1H, d,J=16 Hz), 3.23 (1H, d, J=16 Hz), 3.19 (1H, d, J=16 Hz), 2.17 (3H, d,J=2.4 Hz).

Examples 22 and 23:(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideand(S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Two regioisomersobserved. Preparative HPLC gave(S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off white solid (4 mg); LCMS (ES+) 384 (M+H)⁺, RT 10.09 min(Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.22 (1H, s), 8.80 (1H,br s), 7.62 (1H, s), 7.40-7.00 (6H, m), 3.64 (1H, d, J=16 Hz), 3.51 (1H,d, J=16 Hz), 3.08 (1H, d, J=16 Hz), 3.06 (1H, d, J=16 Hz), 2.18 (6H, s)and also(S)-5-(3-fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off white solid (44 mg); LCMS (ES+) 384 (M+H)⁺, RT 3.62 min(Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.23 (1H, s), 8.82 (1H,br s), 7.42 (1H, s), 7.38-7.00 (6H, m), 3.75 (1H, d, J=16 Hz), 3.43 (1H,d, J=16 Hz), 3.19 (1H, d, J=16 Hz), 2.79 (1H, d, J=16 Hz), 2.11 (3H, d,J=2.8 Hz), 2.04 (3H, s).

Examples 24 and 25:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideand(S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Two regioisomersobserved. Preparative HPLCgave(S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off white solid (47 mg); LCMS (ES+) 366 (M+H)⁺, RT 3.62 min(Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.26 (1H, s), 8.80 (1H,br s), 7.50-7.30 (4H, m), 7.25-7.00 (4H, m), 4.09 (1H, d, J=16 Hz), 3.50(1H, d, J=16 Hz), 3.25 (1H, d, J=16 Hz), 3.14 (1H, d, J=16 Hz), 2.37(3H, s), 2.16 (3H, d, J=2.8 Hz) and also(S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off white solid (39 mg); LCMS (ES+) 366 (M+H)⁺, RT 10.59 min(Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.24 (1H, s), 8.09 (1H,s), 7.58 (1H, s), 7.55-7.50 (1H, m), 7.35-7.25 (1H, m), 7.20-7.00 (5H,m), 3.64 (1H, d, J=16 Hz), 3.50 (1H, d, J=16 Hz), 3.09 (1H, d, J=16 Hz),3.05 (1H, d, J=16 Hz), 2.35 (3H, s), 2.17 (3H, d, J=2.4 Hz).

Examples 26 and 27:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideand(S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. The two pyrazoleregioisomers were separated by preparative HPLC at the carboxylic acidstage and both isomers progressed to the final step. Preparative HPLCgave(S)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off-white solid (27 mg); LCMS (ES+) 367 (M+H)⁺, RT 2.32 min(Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.25 (1H, s), 8.82 (1H,br s), 8.58 (1H, s), 8.51 (1H, d, J=5.2 Hz), 7.55 (1H, s), 7.37 (1H, d,J=5.2 Hz), 7.20-7.00 (3H, m), 3.94 (1H, d, J=16 Hz), 3.45 (1H, d, J=14.8Hz), 3.20 (1H, d, J=13.6 Hz), 3.06 (1H, d, J=16 Hz), 2.31 (3H, s), 2.14(3H, d, J=2.8 Hz).(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideas an off-white solid (29 mg). LCMS (ES+) 367 (M+H)⁺, RT 2.46 min(Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.25 (1H, s), 8.82 (1H,br s), 8.55 (1H, s), 8.47 (1H, d, J=5.2 Hz), 7.96 (1H, s), 7.48 (1H, d,J=5.2 Hz), 7.20-7.00 (3H, m), 3.68 (1H, d, J=16 Hz), 3.53 (1H, d, J=16Hz), 3.14 (1H, d, J=16 Hz), 3.08 (1H, d, J=16 Hz), 2.42 (3H, s), 2.18(3H, d, J=2.8 Hz).

Example 28:(S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. The two pyrazoleregioisomers were separated by preparative HPLC at the carboxylic acidstage and only one regioisomer was progressed. Preparative HPLC gave thetitle compound as an off-white solid (13 mg). LCMS (ES+) 387/389 (M+H)⁺,RT 3.25 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.26 (1H,s), 8.80 (1H, br s), 8.46 (1H, dd, J=4.4 and 1.6 Hz), 8.15 (1H, dd, J=8and 1.6 Hz), 7.95 (1H, s), 7.46 (1H, dd, J=8 and 4.4 Hz), 7.20-7.00 (3H,m), 3.69 (1H, d, J=16 Hz), 3.51 (1H, d, J=16 Hz), 3.14 (1H, d, J=16 Hz),3.08 (1H, d, J=16 Hz), 2.18 (3H, d, J=2.4 Hz).

Example 29:(S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Purification bypreparative HPLC at the carboxylic acid and also the hydroxamic acidstage gave the title compound as an off-white solid (45 mg). LCMS (ES+)371 (M+H)⁺, RT 3.12 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.26 (1H, s), 8.82 (1H, br s), 8.32-8.28 (1H, m), 8.10 (1H, s),7.98-7.90 (1H, m), 7.45-7.40 (1H, m), 7.20-7.00 (3H, m), 3.69 (1H, d,J=16 Hz), 3.51 (1H, d, J=16 Hz), 3.14 (1H, d, J=16 Hz), 3.08 (1H, d,J=16 Hz), 2.18 (3H, d, J=2.4 Hz).

Example 30:(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1 starting fromIntermediate 2. Preparative HPLC gave the title compound as a tan solid(12 mg). LCMS (ES+) 352 (M+H)⁺, RT 3.53 min (Analytical method 1); ¹HNMR δ (ppm)(DMSO-d₆): 10.26 (1H, s), 8.80 (1H, br s), 7.70-7.60 (2H, m),7.55-7.45 (3H, m), 7.30 (1H, m), 7.25-7.00 (3H, m), 4.12 (1H, d), 3.40(1H, d), 3.25 (1 h, d), 3.20 (1H, d), 2.20 (3H, d, J=2.4 Hz).

Examples 31 and 32:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideandE2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

Step 1: Methyl5-(3-fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

Intermediate 6 (515 mg, 1.76 mmol), AcOH (10 mL) and phenylhydrazine(0.174 mL, 1.76 mmol) were combined in a sealed tube and heated to 70°C. for 1 h. Reaction mixture was then evaporated to dryness onto silicaand purified by flash chromatography to give the title compound as ayellow gum (288 mg, 45%). LCMS (ES+) 365 (M+H)⁺; ¹H NMR δ (ppm)(CHCl₃-d)7.58 (1H, s), 7.45-7.35 (4H, m), 7.35-7.25 (1H, m), 7.10-6.85 (3H, m),3.73 (3H, s), 3.31 (1H, d, J=16.4 Hz), 3.12 (1H, d, J=16.4 Hz),2.75-2.65 (1H, m), 2.55-2.30 (2H, m), 2.25-2.10 (1H, m), 2.20 (3H, d,J=2.4 Hz).

Step 2:5-(3-Fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylicacid

Methyl5-(3-fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate(280 mg), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) were combined in asealed tube and heated to 70° C. for 5 days. Reaction was cooled andevaporated to dryness. Residue was partitioned between 1N HCl and EtOAc.Organics were dried (MgSO₄) and evaporated to dryness to give the titlecompound as a tan gum (225 mg, 84%). LCMS (ES+) 351 (M+H)⁺.

Step 3:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideandE2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

5-(3-Fluoro-2-methylphenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylicacid (225 mg, 0.64 mmol), TFFH (185 mg, 0.7 mmol), DMF (2 mL) andtriethylamine (0.28 mL) were combined and stirred for 1 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was thenadded and stirring continued for 2 days. Volatile solvents were removedin vacuo. MeOH (5 mL) and 2N HCl in Et₂O (2 mL) were added and reactionmixture was stirred for 4 h. Volatile solvents were removed in vacuo andremaining crude material was purified by preparative HPLC. Chiralpreparative HPLC gave the E1 and E2 enantiomers (Chiralpak IA, Method50/50 THF (0.1% formic acid)/heptane 5.0 mL/min, RT 5.4 (E1-(abs)) and10.1 min (E2-(abs))). E1-enantiomer was obtained as a white solid (22mg). LCMS (ES+) 366 (M+H)⁺, RT 3.45 min (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 10.21 (1H, s), 8.74 (1H, s), 7.58 (1H, s), 7.50-7.40(4H, m), 7.33-7.27 (1H, m), 7.15-6.95 (3H, m), 3.15-2.98 (2H, m),2.75-2.65 (1H, m), 2.45-2.10 (3H, m), 2.20 (3H, d, J=2.4 Hz).E2-enantiomer was obtained as a white solid (23 mg). LCMS (ES+) 366(M+H)⁺, RT 3.39 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.21 (1H, s), 8.74 (1H, s), 7.58 (1H, s), 7.50-7.40 (4H, m), 7.33-7.27(1H, m), 7.15-6.95 (3H, m), 3.15-2.98 (2H, m), 2.75-2.65 (1H, m),2.45-2.10 (3H, m), 2.20 (3H, d, J=2.4 Hz).

Examples 33 and 34:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamideandE2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

Prepared following the method described for Example 31 and 32. The twoobserved pyrazole regioisomers were separated by flash chromatography atthe carboxylic ester stage and only one regioisomer was progressed.Purification by preparative HPLC followed by chiral preparative HPLCgave the E1 and E2 enantiomers. (Chiralpak IC, Method 10/90 EtOH (0.1%formic acid)/Heptane 5.0 mL/min, RT 21.0 (E1-(abs)) and 15.6 min(E2-(abs))). E1-enantiomer was obtained as an off-white solid (8 mg).LCMS (ES+) 384 (M+H)⁺, RT 3.57 (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 10.22 (1H, br s), 8.73 (1H, s), 8.01 (1H, d, J=2.8 Hz),7.79-7.75 (1H, m), 7.50-7.40 (1H, m), 7.40-7.25 (2H, m), 7.20-7.00 (3H,m), 3.10 (2H, s), 2.70-2.60 (1H, m), 2.45-2.30 (2H, m), 2.20 (3H, d,J=2.8 Hz), 2.15-2.05 (1H, m). E2-enantiomer was obtained as an off-whitesolid (7 mg). LCMS (ES+) 384 (M+H)⁺, RT 3.55 (Analytical method 1); ¹HNMR δ (ppm)(DMSO-d₆): 10.22 (1H, br s), 8.73 (1H, s), 8.01 (1H, d, J=2.8Hz), 7.79-7.75 (1H, m), 7.50-7.40 (1H, m), 7.40-7.25 (2H, m), 7.20-7.00(3H, m), 3.10 (2H, s), 2.70-2.60 (1H, m), 2.45-2.30 (2H, m), 2.20 (3H,d, J=2.8 Hz), 2.15-2.05 (1H, m).

Example 35:5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideand5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

Prepared following the method described for Example 31 and 32. The twoobserved pyrazole regioisomers were obtained as an inseparable mixture.Preparative HPLC gave a regioisomeric racemic mixture of the titlecompounds as an off-white solid (105 mg). LCMS (ES+) 372 (M+H)⁺, RT 9.33(Analytical method 2). ¹H NMR δ (ppm)(DMSO-d₆): 10.18 (0.5H, s), 10.16(0.5H, s), 8.73 (1H, br s), 7.59 (0.5H, s), 7.42 (0.5H, s), 7.15-6.80(3H, m), 5.04-4.86 (2H, m), 3.15-2.85 (2H, m), 2.70-2.50 (1H, m),2.40-2.15 (2H, m), 2.17 (3H, d, J=2.8 Hz), 2.00-1.75 (1H, m).

Example 36:5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideand5-(3-fluoro-2-methylphenyl)-2-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

Prepared following the method described for Example 31 and 32. The twoobserved pyrazole regioisomers were obtained as an inseparable mixture.Purification by preparative HPLC gave a regioisomeric racemic mixture ofthe title compounds as a white solid (29 mg). LCMS (ES+) 398 (M+H)⁺, RT3.36 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.17 (0.5H, s),10.14 (0.5H, s), 8.70 (1H, br s), 7.57 (0.5H, s), 7.36 (0.5H, s),7.30-6.80 (6H, m), 5.19 (1H, s), 5.14 (1H, s), 3.20-2.80 (2H, m),2.65-2.40 (1H, m), 2.40-2.15 (2H, m), 2.16 (1.5H, d, J=2.8 Hz), 2.14(1.5H, d, J=2.8 Hz), 1.90-1.80 (1H, m), 1.65-1.50 (1H, m).

Examples 37 and 38:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideandE2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

Prepared following the method described for Example 31 and 32.Purification by preparative HPLC followed by chiral preparative HPLCgave the E1 and E2 enantiomers. (Chiralpak IA, Method 20/80 EtOH (0.1%formic acid)/heptane 5.0 mL/min, RT 9.4 (E1-(abs)) and 17.0 min(E2-(abs))). E1-enantiomer was obtained as an off white solid (43 mg).LCMS (ES+) 380 (M+H)⁺, RT 3.49 (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 10.19 (1H, s), 8.74 (1H, s), 7.54 (1H, s), 7.35-7.20(3H, m), 7.15-7.00 (3H, m), 7.00-6.90 (1H, m), 3.21 (1H, d, J=16 Hz),2.96 (1H, d, J=16 Hz), 2.40-2.20 (3H, m), 2.15 (3H, d, J=2.8 Hz), 1.79(3H, s), 1.65-1.50 (1H, m). E2-enantiomer was obtained as an off whitesolid (43 mg). LCMS (ES+) 380 (M+H)⁺, RT 3.49 (Analytical method 1); ¹HNMR δ (ppm)(DMSO-d₆): 10.19 (1H, s), 8.74 (1H, s), 7.54 (1H, s),7.35-7.20 (3H, m), 7.15-7.00 (3H, m), 7.00-6.90 (1H, m), 3.21 (1H, d,J=16 Hz), 2.96 (1H, d, J=16 Hz), 2.40-2.20 (3H, m), 2.15 (3H, d, J=2.8Hz), 1.79 (3H, s), 1.65-1.50 (1H, m).

Example 39:3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

Step 1: Methyl5-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylateand methyl5-(3-fluoro-2-methylphenyl)-3-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate

Intermediate 4 (1.12 g, 3.07 mmol), acetic acid (10 mL) and 2, 2,2-trifluoroethyl hydrazine (70% in water) (0.5 mL, 3.1 mmol) werecombined and heated to 65° C. for 19 h. Reaction mixture was evaporatedto dryness onto silica and purified by flash chromatography to give amixture of the title compounds as a clear gum (1.04 g, 88%). LCMS (ES+)387 (M+H)⁺.

Step 2: Methyl5-(3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylateand methyl5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

The crude mixture of methyl5-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylateand methyl5-(3-fluoro-2-methylphenyl)-3-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylate(0.925 mg, 2.39 mmol) from reaction above was combined with DCM (80 mL)and triethylamine (0.5 mL) under nitrogen. The reaction mixture was icebath cooled and trifluoromethanesulfonic anhydride (0.4 mL, 2.4 mmol)was added dropwise. The reaction mixture was stirred with continued icebath cooling for 1 h then evaporated to dryness in vacuo onto silica andpurified by flash chromatography to give methyl5-(3-fluoro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylateas a clear oil (48 mg). LCMS (ES+) 519 (M+H)⁺; and methyl5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylateas a clear oil (639 mg). LCMS (ES+) 519 (M+H)⁺.

Step 3:3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate

Methyl5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate(205 mg, 0.397 mmol), THF (10 mL), cyclopropyl zinc bromide (0.5N inTHF) (4 mL, 2 mmol) and palladium tetrakis triphenylphosphine (10 mg)were combined under a nitrogen atmosphere and heated to 70° C. for 3days. The reaction mixture was then diluted with EtOAc, washed with sat.aq. NH₄Cl soln. and evaporated to dryness in vacuo. The crude productwas purified by preparative HPLC to give the title compound as a tansolid (17.9 mg). LCMS (ES+) 411 (M+H)⁺.

Step 4:3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylicacid

Methyl3-cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylate(17.9 mg), MeOH (7 mL) and 15% NaOH soln. (0.5 mmol) were combined andheated to 70° C. for 15 days. Reaction mixture was then evaporated todryness in vacuo, then partitioned between EtOAc and 1N HCl. Organiclayer was dried (MgSO₄) and evaporated to dryness in vacuo to give thetitle compound (16 mg) as a clear glass. LCMS (ES+) 397 (M+H)⁺.

Step 5:3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxylicacid (16 mg), TFFH (100 mg), DMF (1 mL) and triethylamine (0.5 mL) werecombined and stirred at room temperature for 1 h.0-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (60 mg, 0.5 mmol) was thenadded and stirring continued for 1 day. Volatile solvents were removedin vacuo. MeOH (5 mL) and 2N HCl in Et₂O (2 mL) were added and reactionmixture was stirred for 1 h. Volatile solvents were removed in vacuo andremaining crude material was purified by preparative HPLC to give thetitle compound as a white solid (4 mg). LCMS (ES+) 412 (M+H)⁺, RT 9.89(Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.15 (1H, s), 8.75 (1H,br s), 7.15-6.95 (2H, m), 6.85-6.80 (1H, m), 5.05-4.85 (2H, m), 3.08(1H, d, J=16 Hz), 2.86 (1H, d, J=16 Hz), 2.50-2.40 (1H, m), 2.35-2.25(1H, m), 2.25-2.15 (1H, m), 2.17 (3H, d, J=2.8 Hz), 1.85-1.70 (2H, m),1.05-0.90 (2H, m), 0.85-0.65 (2H, m).

Example 40:2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide

Step 1: Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylate

Intermediate 4 (1 g, 2.74 mmol), cyclopropylcarbamidine. HCl (361 mg, 3mmol), MeOH (20 mL) and DIPEA (1 mL) were combined in a sealed tube andheated to 65° C. for 14 days. Reaction mixture was then evaporated todryness in vacuo onto silica and purified by flash chromatography togive the title compound as a clear glass (99 mg). LCMS (ES+) 357 (M+H)⁺.

Step 2:2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylicacid

Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylate(99 mg), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) were combined in asealed tube and heated to 65° C. for 19 days. The reaction mixture wasthen evaporated to dryness in vacuo, then partitioned between EtOAc and1N HCl. The organic layer was dried (MgSO₄) and evaporated to dryness invacuo to give the title compound as a clear glass (25 mg). LCMS (ES+)343 (M+H)⁺.

Step 3:2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxylicacid (25 mg), TFFH (25 mg), DMF (1 mL) and triethylamine (0.1 mL) werecombined and stirred at room temperature for 2 h.0-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (30 mg, 0.25 mmol) was thenadded and stirring was continued for 2 days. Volatile solvents wereremoved in vacuo. MeOH (2 mL) and 2N HCl in Et₂O (2 mL) were added andthe reaction mixture was stirred for 1.5 h. Volatile solvents wereremoved in vacuo and remaining crude material was purified bypreparative HPLC to give the title compound as an off-white solid (4mg). LCMS (ES+) 358 (M+H)⁺, RT 2.65 (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 12.44 (1H, s), 10.17 (1H, s), 8.71 (1H, s), 7.20-6.95(2H, m), 6.90-6.80 (1H, m), 3.55-3.40 (1H, m), 2.70-2.60 (1H, mO,2.40-2.30 (1H, m), 2.30-2.15 (2H, m), 2.17 (3H, d, J=2.8 Hz), 1.95-1.75(2H, m), 1.00-0.85 (4H, m).

Example 41:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

Step 1: Methyl6-(3-fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

Intermediate 7 (200 mg, 0.625 mmol), pyridine (5 mL), and phenylsulfonylchloride (0.091 mL, 0.65 mmol) were combined and stirred for 4 days.Reaction mixture was then diluted with EtOAc, washed with 1N HCl (2×),dried (MgSO₄) and evaporated to dryness to give the title compound as atan solid (234 mg, 81%). LCMS (ES+) 461 (M+H)⁺.

Step 2:6-(3-Fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid

Methyl6-(3-fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate(230 mg, 0.5 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) werecombined in a sealed tube and heated to 70° C. for 5 days. Reaction wascooled and evaporated to dryness. Residue was partitioned between 1N HCland EtOAc. Organics were dried (MgSO₄) and evaporated to dryness to givethe title compound as a yellow gum (181 mg, 81%). LCMS (ES+) 447 (M+H)⁺.

Step 3:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

6-(3-Fluoro-2-methylphenyl)-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid (181 mg, 0.4 mmol), TFFH (127 mg, 0.48 mmol), DMF (2 mL) andtriethylamine (0.5 mL) were combined and stirred for 16 h.0-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was thenadded and stirring continued for 2 days. Volatile solvents were removedin vacuo. MeOH (5 mL) and 2N HCl in Et₂O (2 mL) were added and reactionmixture was stirred for 2 h. Volatile solvents were removed in vacuo andremaining crude material was purified by preparative HPLC to give thetitle compound as an off-white solid (26 mg). LCMS (ES+) 462 (M+H)⁺, RT9.49 (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 12.45 (1H, br s),10.22 (1H, s), 8.77 (1H, s), 7.82 (2H, m), 7.65-7.50 (3H, m), 7.25-7.10(1H, m), 7.10-7.00 (1H, m), 6.95-6.85 (1H, m), 3.10-2.95 (1H, m),2.85-2.75 (1H, m), 2.45-2.25 (3H, m), 2.15 (3H, d, J=2.4 Hz), 1.95-1.75(1H, m).

Example 42:2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

Step 1: Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

Intermediate 8 (300 mg, 0.78 mmol), THF (10 mL),tetrakis(triphenylphosphine)palladium(0) (10 mg) and cyclopropylzincbromide (0.5N in THF) (3 mL, 1.5 mmol) were combined under a nitrogenatmosphere and heated to 60° C. for 16 h. Furthertetrakis(triphenylphosphine)palladium(0) (20 mg) and cyclopropylzincbromide (0.5N in THF) (3 mL, 1.5 mmol) were added and heating continuedfor 23 h. The reaction mixture was evaporated to dryness onto silica andpurified by flash chromatography to give the title compound as a tansolid (177 mg, 66%). LCMS (ES+) 346 (M+H)+.

Step 2:2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid

Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate(170 mg, 0.49 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (1 mL) werecombined in a sealed tube and heated to 65° C. for 5 days. Reaction wascooled and evaporated to dryness. Residue was partitioned between 1N HCland EtOAc. The organic phase was dried (MgSO₄) and evaporated to drynessto give the title compound as a grey solid (136 mg, 84%). LCMS (ES+) 332(M+H)⁺.

Step 3:2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid (136 mg, 0.41 mmol), TFFH (132 mg, 0.5 mmol), DMF (2 mL) andtriethylamine (2 mL) were combined and stirred for 1.5 h.0-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was thenadded and stirring continued for 1 day. Volatile solvents were removedin vacuo. MeOH (2 mL) and 2N HCl in Et₂O (2 mL) were added and reactionmixture was stirred for 2 h. Volatile solvents were removed in vacuo andremaining crude material was purified by preparative HPLC to give thetitle compound as a yellow glass (54 mg). LCMS (ES+) 347 (M+H)⁺, RT 3.2(Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.21 (1H, s), 8.80 (1H,br s), 7.15-7.05 (2H, m), 6.90 (1H, m), 3.30-3.05 (2H, m), 2.65-2.50(1H, m), 2.40-2.25 (3H, m), 2.20 (3H, d, J=2.4 Hz), 2.10-2.00 (1H, m),1.10-1.00 (2H, m), 1.90-1.80 (2H, m).

Example 43:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

Step 1: Methyl6-(3-fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

Intermediate 8 (275 mg, 0.716 mmol), pyrimidine-5-boronic acid (99 mg,0.8 mmol), CsF (150 mg), DME (15 mL), MeOH (2 mL) andtetrakis(triphenylphosphine)palladium(0) (10 mg) were combined in asealed tube and microwave heated to 120° C. for 2 h. Reaction mixturewas evaporated to dryness onto silica and purified by flashchromatography to give the title compound as a tan glass (217 mg, 79%).LCMS (ES+) 384 (M+H)⁺.

Step 2:6-(3-Fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid

Methyl6-(3-fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate(200 mg, 0.52 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (1 mL) werecombined in a sealed tube and heated to 65° C. for 2 days. The reactionmixture was cooled and evaporated to dryness. Residue was partitionedbetween AcOH/H₂O and EtOAc. The organic phase was dried (MgSO₄) andevaporated to dryness to give the title compound as a pale yellow glass(151 mg) which was used crude in next step.

Step 3:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

6-(3-Fluoro-2-methylphenyl)-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid (151 mg, 0.4 mmol), TFFH (132 mg, 0.5 mmol), DMF (2 mL) andtriethylamine (2 mL) were combined and stirred for 1 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was thenadded and stirring continued for 1 day. Volatile solvents were removedin vacuo. MeOH (2 mL) and 2N HCl in Et₂O (2 mL) were added and reactionmixture was stirred for 30 min. Volatile solvents were removed in vacuoand remaining crude material was purified by preparative HPLC to givethe title compound as an off white solid (11 mg). LCMS (ES+) 385 (M+H)⁺,RT 9.03 (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.30 (1H, s),9.25 (1H, s), 9.24 (2H, s), 8.80 (1H, s), 7.20-6.95 (3H, m), 3.55-3.45(1H, m), 3.30-3.15 (1H, m), 2.80-2.70 (1H, m), 2.60-2.40 (2H, m),2.40-2.30 (1H, m), 2.20 (3H, d, J=2.4 Hz).

Example 44:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

Step 1: Methyl6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate

Intermediate 8 (300 mg, 0.78 mmol), AcOH (10 mL) and Zn dust (300 mg)were combined and heated to 65° C. for 1 h. Zn residues were removed byfiltering through a celite plug washing through with EtOAc. Organicswere then evaporated to dryness to give the title compound as a tansolid which was used crude in next step. LCMS (ES+) 306 (M+H)⁺.

Step 2:6-(3-Fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid

Methyl6-(3-fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylate(0.78 mmol), MeOH (15 mL) and 15% aq. NaOH soln. (3 mL) were combined ina sealed tube and heated to 65° C. for 19 h. Reaction was cooled andevaporated to dryness. The residue was partitioned between 1N HCl andEtOAc. Organics were dried (MgSO₄) and evaporated to dryness to give thetitle compound as a tan glass (191 mg, 84% over two steps). LCMS (ES+)292 (M+H)⁺.

Step 3:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide

6-(3-Fluoro-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxylicacid (196 mg, 0.67 mmol), TFFH (264 mg, 1 mmol), DMF (2 mL) andtriethylamine (0.3 mL) were combined and stirred for 1 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was thenadded and stirring continued for 2 days. Volatile solvents were removedin vacuo. MeOH (2 mL) and 2N HCl in Et₂O (2 mL) were added and reactionmixture was stirred for 5 h. Volatile solvents were removed in vacuo andremaining crude material was purified by preparative HPLC to give thetitle compound as an off-white solid (43 mg). LCMS (ES+) 307 (M+H)⁺, RT2.87 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.24 (1H, s), 8.86(1H, s), 8.77 (1H, s), 7.15-7.00 (2H, m), 6.90 (1H, m), 3.40-3.30 (1H,m), 3.25-3.15 (1H, m), 2.75-2.65 (1H, m), 2.60-2.50 (1H, m), 2.45-2.35(1H, m), 2.25-2.10 (1H, m), 2.20 (3H, d, J=2.4 Hz).

Example 45:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide

Step 1: Methyl6-(3-fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylate

Intermediate 6 (516 mg, 1.77 mmol), formamidine.AcOH (198 mg, 1.9 mmol),MeOH (10 mL) and DIPEA (2 mL) were combined in a sealed tube and heatedto 70° C. for 2.5 h. The reaction mixture was then evaporated to drynessonto silica and purified by flash chromatography to give the titlecompound as a clear gum (264 mg, 50%). LCMS (ES+) 301 (M+H)⁺.

Step 2:6-(3-Fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylicacid

Methyl6-(3-fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylate(264 mg, 0.88 mmol), MeOH (10 mL) and 15% aq. NaOH soln. (2 mL) werecombined in a sealed tube and heated to 70° C. for 4 days. The reactionmixture was cooled and evaporated to dryness. The residue waspartitioned between 1N HCl and EtOAc. Organics were dried (MgSO₄) andevaporated to dryness to give the title compound as a pale yellow gum(194 mg, 77%). LCMS (ES+) 287 (M+H)⁺.

Step 3:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide

6-(3-Fluoro-2-methylphenyl)-5,6,7,8-tetrahydroquinazoline-6-carboxylicacid (194 mg, 0.68 mmol), TFFH (211 mg, 0.8 mmol), DMF (2 mL) andtriethylamine (0.28 mL) were combined and stirred for 4 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (117 mg, 1 mmol) was thenadded and stirring continued for 16 h. Volatile solvents were removed invacuo. MeOH (5 mL) and 2N HCl in Et₂O (2 mL) were added and reactionmixture was stirred for 2.5 h. Volatile solvents were removed in vacuoand remaining crude material was purified by preparative HPLC to givethe title compound as a white solid (17 mg). LCMS (ES+) 302 (M+H)⁺, RT2.59 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.28 (1H, s), 8.85(1H, s), 8.76 (1H, s), 8.57 (1H, s), 7.25-7.00 (3H, m), 3.50-3.35 (1H,m), 3.00-2.90 (1H, m), 2.80-2.70 (1H, m), 2.65-2.55 (1H, m), 2.50-2.40(2H, m), 2.21 (3H, d, J=2.4 Hz).

Example 46:2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide

Prepared following the method described for Example 45. Preparative HPLCgave the title compound as a white solid (90 mg). LCMS (ES+) 342 (M+H)⁺,RT 2.96 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.28 (1H, s),8.75 (1H, br s), 8.39 (1H, s), 7.20-6.95 (3H, m), 3.40-3.30 (2H, m), 2.9(1H, m), 2.75-2.65 (1H, m), 2.50-2.35 (2H, m), 2.21 (3H, d, J=2.4 Hz),2.10 (1H, m), 1.00-0.85 (4H, m).

Example 47:6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxamide

Prepared following the method described for Example 45. Preparative HPLCgave the title compound as a white solid (53 mg). LCMS (ES+) 378 (M+H)⁺,RT 3.66 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.31 (1H, s),8.78 (1H, br s), 8.68 (1H, s), 8.35 (2H, m), 7.55-7.45 (3H, m),7.25-7.00 (3H, m), 3.50-3.40 (2H, m), 3.05-2.95 (1H, m), 2.90-2.80 (1H,m), 2.70-2.55 (2H, m), 2.24 (3H, d, J=2.4 Hz).

Examples 48 and 49:(S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamideand(R)-2-(2-chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

Step 1:(S)-Methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate and(R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate

Intermediate 3 (2.5 g, 1.0 mmol) was dissolved in dimethylformamidedimethylacetal (5.0 mL) and heated to 80° C. for 16 h. The cooledmixture was concentrated onto silica and purified by flash silica columnchromatography (gradient elution i-hex to 100% EtOAc in i-hex) to yieldthe title compounds as a pale yellow oil (1.8 g, 58%). LCMS (ES+) 306(M+H)⁺.

Step 2: Methyl(6S)-2-(2-chlorophenyl)-6-(3-fluoro-2-methyl-phenyl)-5,7-dihydrocyclopenta[d]pyrimidine-6-carboxylateand methyl(5R)-2-(2-chlorophenyl)-5-(3-fluoro-2-methyl-phenyl)-6,7-dihydrocyclopenta[d]pyrimidine-5-carboxylate

A mixture of(S)-methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate and(R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate(0.305 g, 1 mmol) and 2-chlorobenzamidine hydrochloride (0.28 g, 1.5mmol) in methanol (5 mL) was heated to 130° C. for 30 min. The solventwas removed under reduced pressure and the residue was partitionedbetween DCM (15 mL) and water (15 mL). The DCM was separated (phaseseparator) and evaporated under reduced pressure to give an oil whichwas purified by flash chromatography to give (S)-methyl2-(2-chlorophenyl)-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylateas a colorless oil. LCMS (ES+) 397 (M+H)⁺; ¹H NMR δ (ppm)(CHCl₃-d): 8.68(1H, s), 7.74-7.68 (1H, m), 7.53-7.47 (1H, m), 7.40-7.33 (2H, m),7.19-7.06 (1H, m), 7.07-6.94 (2H, m), 4.07-3.94 (2H, m), 3.73 (3H, s),3.63 (1H, s), 3.59-3.48 (1H, m), 2.23 (3H, s). (R)-Methyl2-(2-chlorophenyl)-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylatewas obtained as a colorless oil. LCMS (ES+) 398 (M+H)⁺; ¹H NMR δ(ppm)(CHCl₃-d): 8.83 (1H, s), 7.81-7.75 (1H, m), 7.55-7.48 (1H, m),7.48-7.26 (2H, m), 7.16-7.04 (1H, m), 7.01 (1H, m), 6.56 (1H, m), 3.79(3H, s), 3.51 (1H, m), 3.30 (1H, m), 3.12 (1H, m), 2.27-2.18 (4H, m).

Step 3:(S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

Trimethylaluminum (1.56 mL, 2 M in toluene, 3.12 mmol) was added to astirred solution of hydroxylamine hydrochloride (240 mg, 10.1 mmol) indry DCM (5 mL) under nitrogen and the resulting solution was stirred for30 min at room temperature under nitrogen. A solution of(65)-2-(2-chlorophenyl)-6-(3-fluoro-2-methyl-phenyl)-5,7-dihydrocyclopenta[d]pyrimidine-6-carboxylate(0.234 g, 0.59 mmol) in DCM (8 mL) was added and stirring was continuedfor 1 h. Saturated ammonium chloride solution (1 mL) was added followedby water (2.5 mL) and the resulting mixture was evaporated to dryness,the residue was stirred with methanol (25 mL) for 10 min. and filtered.The filtrate was evaporated to dryness under reduced pressure and theresidue was stirred with EtOAc (30 mL) and filtered. The EtOAc wasevaporated and the resulting oil was purified by preparative HPLC togive the title compound (78 mg, 33%) as a colorless solid. LCMS (ES+)398 (M+H)⁺, RT 3.44 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.30 (1H, br), 8.86 (1H, br), 8.81-8.69 (1H, m), 7.73-7.65 (1H, m),7.59-7.53 (1H, m), 7.51-7.42 (2H, m), 7.24-7.05 (3H, m), 3.98-3.93 (1H,m), 3.84-3.78 (1H, m), 3.53-3.47 (1H, m), 3.43-3.23 (1H, m), 2.27-2.19(3H, m).

Step 4:(R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

The same method as for Step 3 from (R)-methyl2-(2-chlorophenyl)-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate.Preparative HPLC gave the title compound (14 mg) as a colorless solid.LCMS (ES+) 398 (M+H)⁺, RT 8.91 (Analytical method 3); ¹H NMR δ(ppm)(DMSO-d₆): 8.95 (1H, s), 7.79-7.75 (1H, m), 7.63-7.58 (1H, m),7.55-7.46 (2H, m), 7.21-7.11 (2H, m), 6.63 (1H, s), 3.5-3.30 (1H, m),3.20-3.05 (1H, m), 3.05-2.96 (1H, m), 2.19 (3H, d, J=2 Hz), 2.07-1.98(1H, m), two exchangeable protons not seen.

Examples 50 and 51:(R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamideand(S)-2-cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

Step 1:(R)-Methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate and(S)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate

Intermediate 2 (2.5 g, 1.0 mmol) was dissolved in dimethylformamidedimethylacetal (5.0 mL) and heated to 80° C. for 16 h. Concentrated ontosilica and purified by flash silica column chromatography (gradientelution i-hex to 100% EtOAc in i-hex) to yield the title compounds as apale yellow oil (1.8 g, 58.8%). LCMS (ES+) 306 (M+H)⁺.

Step 2: (R)-Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylateand (S)-methyl2-cyclopropyl-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate

To a solution of(R)-methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate and(S)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate(0.23 g, 0.75 mmol) in methanol (10 mL) was addedcyclopropanecarboximidamide (91 mg, 0.755 mmol) and NaOMe (41 mg, 0.755mmol) and the reaction mixture was stirred at 100° C. overnight. Themixture was concentrated onto silica and purified by flash silica columnchromatography (gradient elution i-hex to 70% EtOAc in i-hex) to yield(R)-methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylateasa yellow oil (0.12 g, 50%). LCMS (ES+) 327 (M+H)⁺. (S)-Methyl2-cyclopropyl-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylatewasobtained as a yellow oil (68 mg, 28%). LCMS (ES+) 327 (M+H)⁺.

Step 3:(R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylicacid

(R)-Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate(68 mg, 0.19 mmol), MeOH (3 mL) and 15% aq. NaOH soln. (0.5 mL) werecombined in a sealed tube and heated to 70° C. for 4 days. The reactionmixture was cooled and evaporated to dryness. The residue waspartitioned between 1N HCl and EtOAc. Organics were dried (MgSO₄) andevaporated to dryness to give the title compound as an off white solid.LCMS (ES+) 313 (M+H)⁺.

Step 4:(S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylicacid

Following the same method as Step 3. Preparative HPLC gave the titlecompound as a white solid. LCMS (ES+) 313 (M+H)⁺.

Step 5:(R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

(R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylicacid (51 mg, 0.19 mmol), TFFH (58 mg, 0.22 mmol), DMF (1 mL) andtriethylamine (1 mL) were combined and stirred for 1 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (51 mg, 0.28 mmol) was thenadded and stirring continued for 1 day. Volatile solvents were removedin vacuo. MeOH (1 mL) and 2N HCl in Et₂O (1 mL) were added and reactionmixture was stirred for 30 min. Volatile solvents were removed in vacuoand remaining crude material was purified by preparative HPLC to givethe title compound as an off white solid (29 mg). LCMS (ES+) 328 (M+H)⁺,RT 2.90 (Analytical method 1); ¹H NMR δ (ppm)(CH₃OH-d₄): 8.39 (1H, s),7.19-7.10 (1H, m), 7.09-6.97 (2H, m), 3.90 (1H, d, J=17.2 Hz), 3.80 (1H,d, J=16.4 Hz), 3.44 (1H, d, J=16.4 Hz), 3.29 (1H, d, J=17.2 Hz), 2.26(3H, s), 2.22-2.13 (1H, m), 1.12-1.04 (4H, m) two exchangeable protonsnot seen.

Step 6:(S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

Following the same method as Step 5. Preparative HPLC gave the titlecompound as a white solid (28 mg). LCMS (ES+) 328 (M+H)⁺, RT 9.15(Analytical method 2). ¹H NMR δ (ppm)(CH₃OH-d₄): 8.59 (1H, s), 7.16-7.08(1H, m), 7.05 (1H, t, J=9.0 Hz), 6.54 (1H, d, J=7.78 Hz), 3.50 (1H, ddd,J=13.20, 9.30, 7.12 Hz), 3.16-3.05 (1H, m), 2.92 (1H, ddd, J=17.9, 9.2,7.2 Hz), 2.32-2.23 (4H, m), 2.11 (1H, ddd, J=13.1, 9.2, 4.9 Hz),1.22-1.10 (4H, m) two exchangeable protons not seen.

Example 52:(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

Prepared following the method described for Examples 50 and 51, fromIntermediate 3. Purification by preparative HPLC gave the title compoundas a white solid (12 mg). LCMS (ES+) 328 (M+H)⁺, RT 8.81 (Analyticalmethod 2). ¹H NMR δ (ppm)(DMSO-d₆): 10.24 (1H, s), 8.81 (1H, s), 8.43(1H, s), 7.19-7.12 (1H, m), 7.09-7.03 (2H, m), 3.81 (1H, d, J=17.1 Hz),3.65 (1H, d, J=16.3 Hz), 3.38 (1H, obscured by water), 3.17 (1H, d,J=17.2 Hz), 2.18 (3H, d, J=2.8 Hz), 2.16-2.11 (1H, m), 1.00-0.92 (4H,m).

Example 53:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-isopropyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 50 and 51, startingfrom intermediate 3. Only one regioisomer was isolated. Preparative HPLCgave the title compound as a white solid (5 mg). LCMS (ES+) 318 (M+H)⁺,RT 8.89 (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.18 (1H, s),8.77 (1H, br s), 7.20-6.90 (4H, m), 4.40-4.30 (1H, m), 3.74 (1H, d, J=16Hz), 3.30 (1H, d, J=16 Hz), 3.02 (1H, d, J=16 Hz), 2.98 (1H, d, J=16Hz), 2.15 (3H, d, J=2.8 Hz), 1.35 (6H, d, J=6.8 Hz).

Example 54:(R)-4-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

Prepared following the method described for Example 48 and 49. Only oneregioisomer was isolated. Preparative HPLC gave the title compound as awhite solid (11 mg). LCMS (ES+) 352 (M+H)⁺, RT 9.08 (Analytical method3). ¹H NMR δ (ppm)(DMSO-d₆): 10.21 (1H, s), 8.80 (1H, br s), 8.78 (1H,s), 7.76-7.66 (3H, m), 7.55-7.47 (2H, m), 7.35-7.30 (1H, m), 7.22-7.14(1H, m), 7.13-7.04 (2H, m), 3.95-3.80 (1H, m), 3.22-3.12 (1H, m),3.11-3.02 (1H, m), 2.42-2.33 (1H, m), 2.15 (3H, s).

Example 55:(S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

Prepared following the method described for Example 50 and 51 startingfrom intermediate 3. Only one regioisomer was isolated. Preparative HPLCgave the title compound as an off white solid (23 mg). LCMS (ES+) 382(M+H)⁺, RT 10.55 (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.30(1H, s), 8.80 (1H, br s), 8.72 (1H, s), 8.44-8.37 (2H, m), 7.38-7.28(2H, m), 7.21-7.04 (3H, m), 3.95 (1H, d, J=17.2 Hz), 3.76 (1H, d, J=16.8Hz), 3.47 (1H, d, 16.8 Hz), 3.29 (1H, d, J=17.2 Hz), 2.26-2.20 (3H, s).

Example 56:(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

Prepared following the method described for Example 50 and 51 startingfrom intermediate 3. Only one regioisomer was isolated. Preparative HPLCgave the title compound as a colorless solid (35 mg). LCMS (ES+) 356(M+H)⁺, RT 3.40 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.30(1H, s), 8.87 (2H, s), 7.23-7.14 (1H, m), 7.14-7.05 (2H, m), 4.02-3.97(1H, m), 3.85-3.80 (1H, m), 3.60-3.56 (1H, m), 3.46-3.42 (1H, m), 2.20(3H, s).

Example 57:(R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide

Prepared following the method described for Example 50 and 51 startingfrom intermediate 3. Only one regioisomer was isolated. Preparative HPLCgave the title compound as a colorless solid (21 mg). LCMS (ES+) 328(M+H)⁺, RT 3.17 (Analytical method 1), ¹H NMR δ (ppm)(CH₃OH-d₄): 8.59(1H, s), 7.16-7.00 (2H, m), 6.54 (1H, d, J=7.8 Hz), 3.56-3.44 (1H, m),3.18-3.06 (1H, m), 2.98-2.85 (1H, m), 2.32-2.23 (4H, m), 2.11-2.05 (1H,m), 1.22-1.09 (4H, m) two exchangeable protons not seen.

Examples 58 and 59:(S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamideand(R)-1-cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

Prepared following the method described for Example 50 and 51 startingfrom intermediate 3. Preparative HPLCgave(S)-1-cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamidewas obtained as a white solid (10 mg). LCMS (ES+) 316 (M+H)⁺, RT 7.86(Analytical method 3). ¹H NMR δ (ppm)(DMSO-d₆): 10.19 (1H, s), 8.78 (1H,s), 7.20-7.01 (4H, m), 3.76 (1H, d, J=16 Hz), 3.53-3.45 (1H, m), 3.26(1H, d, J=14.8 Hz), 3.05 (1H, d, J=16 Hz), 2.95 (1H, d, J=14.8 Hz),2.18-2.11 (3H, m), 0.97-0.87 (4H, m).(R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamidewas obtained as a white solid (8 mg). LCMS (ES+) 316 (M+H)⁺, RT 8.22(Analytical method 3). ¹H NMR δ (ppm)(DMSO-d₆): 10.07 (1H, s), 8.68 (1H,s), 7.39 (1H, s), 7.18-7.09 (1H, m), 7.09-7.02 (2H, m), 3.80 (1H, ddd,J=13.1, 8.7, 3.9 Hz), 3.56-3.48 (1H, m), 2.91-2.81 (1H, m), 2.77-2.67(1H, m), 2.31-2.21 (1H, m), 2.10 (3H, d, =16 Hz), 1.04-0.90 (4H, m).

Example 60:(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide

Prepared following the method described for Example 50 and 51, startingfrom intermediate 3. Only one regioisomer was isolated. Preparative HPLCgave the title compound as a white solid (9 mg). LCMS (ES+) 365 (M+H)⁺,RT 2.50 (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.32 (1H, s),9.5 (1H, s), 8.89 (1H, s), 8.8 (1H, s), 8.72-8.64 (2H, m), 8.64 (1H, s),7.60-7.53 (1H, m), 7.21-7.06 (2H, m), 4.03-3.97 (1H, m), 3.84-3.76 (1H,m), 3.57-3.41 (2H, m), 2.24-2.19 (3H, s).

Examples 61 and 62:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideandE2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Step 1: (±)-Methyl5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

To a solution of Intermediate 11 (500 mg, 1.52 mmol) in ethanol (5 mL)was added 2-fluorobenzothioamide (283 mg, 1.82 mmol). The reactionmixture was heated to 110° C. under microwave irradiation for 1 h. Thereaction mixture was concentrated to give a yellow gum. The crudereaction material was purified by flash silica chromatography (gradientelution, 0-40% EtOAc in iso-hexane) to give the title compound as a paleyellow gum (190 mg, 0.49 mmol, 32%). LCMS (ES+) 386 (M+H)⁺; ¹H NMR δ(ppm)(400 MHz, CDCl₃): 8.20 (1H, dt, J=7.9, 7.5 Hz), 7.24-7.10 (5H, m),7.00-6.96 (1H, m), 4.01 (1H, d, J=16.0 Hz), 3.85 (1H, d, J=16.0 Hz),3.74 (3H, s), 3.49 (1H, d, J=16.0 Hz), 3.39 (1H, d, J=16.0 Hz), 2.20(3H, d, J=2.7 Hz).

Step 2:(±)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid

(±)-Methyl5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate(180 mg, 0.46 mmol), methanol (5 mL) and NaOH (3.75 M in water, 1.25 mL,4.69 mmol) were combined in a sealed tube and heated to 65° C. for 18 h.The yellow reaction mixture was concentrated in vacuo. The residue wasdissolved in H₂O (20 mL) and the solution adjusted to pH 7 with 1 M HCl.The aqueous mixture was extracted with EtOAc (2×20 mL); the organicextracts were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by flash silica chromatography (gradient elution, 0-100% EtOAcin iso-hexane) to give the title compound as a yellow gum (180 mg, 0.49mmol, 98%), which was used without further purification.

Step 3:E2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideandE1-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid (180 mg, 0.485 mmol), TFFH (148 mg, 0.56 mmol), DMF (2 mL) andtriethylamine (2 mL) were combined and stirred for 1 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (130 mg, 0.71 mmol) was thenadded and stirring continued for 1 day. Volatile solvents were removedin vacuo. MeOH (2 mL) and 2N HCl in Et₂O (2 mL) were added and thereaction mixture was stirred for 30 min. Volatile solvents were removedin vacuo and remaining crude material was purified by preparative HPLCand chiral HPLC to give the title compounds as off-white solids.(Chiralpak IA, Method 50/50 IPA/MeOH (50/50/0.1% formic acid)/Heptane1.0 mL/min, RT 5.55 min (proposed (E2-(abs)) enantiomer) and 20.58 min.(proposed (E1-(abs)-enantiomer)).(E2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide(27 mg). LCMS (ES+) 387 (M+H)⁺, RT 10.82 min (Analytical method 2); ¹HNMR δ (ppm)(400 MHz, DMSO-d₆): 10.27 (1H, s), 8.82 (1H, s), 8.13 (1H,td, J=7.8, 1.8 Hz), 7.51-7.44 (1H, m), 7.41-7.28 (2H, m), 7.19-7.02 (3H,m), 3.77 (2H, dd, J=16.0, 11.9 Hz), 3.40 (1H, d, J=16.5 Hz), 3.21 (1H,d, J=16.0 Hz), 2.15 (3H, d, J=2.7 Hz). And(E1-(abs)-5-(3-fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide(32 mg). LCMS (ES+) 387 (M+H)⁺, RT 10.82 min (Analytical method 2); ¹HNMR δ (ppm)(400 MHz, DMSO-d₆): 10.27 (1H, s), 8.82 (1H, s), 8.13 (1H,td, J=7.8, 1.8 Hz), 7.51-7.44 (1H, m), 7.41-7.28 (2H, m), 7.19-7.02 (3H,m), 3.77 (2H, dd, J=16.0, 11.9 Hz), 3.40 (1H, d, J=16.5 Hz), 3.21 (1H,d, J=16.0 Hz), 2.15 (3H, d, J=2.7 Hz).

Example 63:5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Prepared following the same method as for Example 61 and 62.Purification by preparative HPLC gave the title compound as an off-whitesolid (12 mg). LCMS (ES+) 451 (M+H)⁺, RT 11.05 min (Analytical method2); ¹H NMR δ (ppm)(DMSO-d₆): 10.22 (1H, s), 8.80 (1H, s), 7.72 (1H, s),7.67-7.61 (2H, m), 7.61-7.54 (1H, m), 7.19-7.11 (1H, m), 7.11-7.01 (2H,m), 4.41 (2H, s), 3.65 (2H, d, J=15.6 Hz), 3.26 (1H, d, J=16.0 Hz), 3.09(1H, d, J=15.6 Hz), 2.13 (3H, d, J=2.7 Hz).

Examples 64 and 65:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideandE2-(abs)-5-(3-fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Prepared following the same method as for Example 61 and 62.Purification by preparative HPLC and chiral HPLC gave the titlecompounds as off-white solids (30 mg and 24 mg, respectively).(Chiralpak IA, Method 50/50 IPA/MeOH (50/50/0.1% formic acid)/Heptane1.0 mL/min, RT 6.73 min (proposed E2-(abs) enantiomer) and 17.40 min.(proposed E1-(abs) enantiomer)); E2-(abs)-enantiomer: LCMS (ES+) 387(M+H)⁺, RT 10.90 min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆):10.27 (1H, s), 8.82 (1H, s), 7.71-7.61 (2H, m), 7.54-7.47 (1H, m), 7.28(1H, td, J=8.5, 2.7 Hz), 7.18-7.02 (3H, m), 3.75 (2H, dd, J=21.0, 16.4Hz), 3.31 (1H, d, J=16.4 Hz), 3.20 (1H, d, J=15.6 Hz), 2.15 (3H, d,J=2.7 Hz). E1-(abs)-enantiomer: LCMS (ES+) 387 (M+H)⁺, RT 10.90 min(Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.27 (1H, s), 8.82 (1H,s), 7.71-7.61 (2H, m), 7.54-7.47 (1H, m), 7.28 (1H, td, J=8.5, 2.7 Hz),7.18-7.02 (3H, m), 3.75 (2H, dd, J=21.0, 16.4 Hz), 3.31 (1H, d, J=16.4Hz), 3.20 (1H, d, J=15.6 Hz), 2.15 (3H, d, J=2.7 Hz).

Example 66:(R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Prepared following the same method as for Example 61 and 62 startingfrom Intermediate 15. Purification by preparative HPLC gave the titlecompound as a white solid(54 mg). LCMS (ES+) 387 (M+H)⁺, RT 10.85 min(Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.29 (1H, s), 8.84 (1H,s), 7.95-7.89 (2H, m), 7.32 (2H, t, J=8.8 Hz), 7.21-7.05 (3H, m), 3.76(2H, t, J=17.7 Hz), 3.37 (1H, d, J=16.5 Hz), 3.20 (1H, d, J=15.5 Hz),2.17 (3H, d, J=2.7 Hz).

Examples 66 and 67:(R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideand(S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Step 1: Methyl5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

A suspension of Intermediate 12 (50 mg, 0.14 mmol), 4-fluorophenylboronic acid (20.6 mg, 0.15 mmol),tetrakis(triphenylphosphine)palladium(0) (23.6 mg, 0.02 mmol) and Cs₂CO₃(278 mg, 0.85 mmol) in dioxane (0.6 mL) and water (0.1 mL) was purgedwith N₂ and stirred at 100° C. for 17 h. The mixture was purified byflash silica chromatography (gradient elution of 0% to 100% EtOAc ini-hex) to give the title compound as a pale yellow liquid (15 mg, 39μmol, 29%).

Step 2:5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid

A suspension of methyl5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate(50 mg, 0.13 mmol) and KOH (111 mg, 1.98 mmol) in MeOH (1 mL) wasstirred at 65° C. for 16 h. The reaction was acidified to pH 1 using 1 MHCl, then extracted with DCM (20 mL). The organic layer was dried bypassage through a phase separator and concentrated to yield 40 mg of ayellow liquid that was used without further purification.

Step 3:(R)-5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideand(S)-5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

A stirred solution of5-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid (˜40 mg of mixture from previous step) in DCM (1 mL) at r.t wastreated with oxalyl chloride (10 μL, 0.12 mmol) and DMF (10 μL) andstirred for 30 min until effervescence ceased. MeCN (1 mL) and aqueoushydroxylamine (50 wt % hydroxylamine, 20 μL, 0.33 mmol) were added andthe reaction heated to 100° C. under microwave irradiation for 10 min.The mixture was concentrated and purification by preparative HPLC andchiral preparative HPLC gave the title compounds (15 mg and 19 mg,respectively). (Chiralpak IA, Method 50/50 IPA/MeOH (50/50/0.1% formicacid)/heptane 1.0 mL/min, RT 6.1 min ((R) enantiomer) and 18.0 min ((S)enantiomer). (R)-Enantiomer LCMS (ES+) 387 (M+H)⁺, RT 10.85 min(Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.29 (1H, s), 8.84 (1H,s), 7.95-7.89 (2H, m), 7.32 (2H, t, J=8.8 Hz), 7.21-7.05 (3H, m), 3.76(2H, t, J=17.7 Hz), 3.37 (1H, d, J=16.5 Hz), 3.20 (1H, d, J=15.5 Hz),2.17 (3H, d, J=2.7 Hz). (S)-Enantiomer: LCMS (ES+) 387 (M+H)⁺, RT 10.85min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.29 (1H, s), 8.84(1H, s), 7.96-7.90 (2H, m), 7.32 (2H, t, J=8.8 Hz), 7.20-7.05 (3H, m),3.76 (2H, t, J=17.7 Hz), 3.37 (2H, d, J=16.5 Hz), 3.20 (1H, d, J=15.5Hz), 2.17 (3H, d, J=2.7 Hz).

Example 68:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Step 1: (S)-Methyl5-(3-fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

A suspension of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(529 mg, 2.54 mmol), Intermediate 14 (620 mg, 1.67 mmol),tetrakis(triphenylphosphine)palladium(0) (93 mg, 80 μmol) and CsF (398mg, 2.62 mmol) in DME (11 mL) and MeOH (2.7 mL) was purged with N₂ andstirred in a microwave reactor at 120° C. for 10 min. The mixture wasconcentrated and purified by flash silica chromatography (gradientelution of 0% to 100% EtOAc in i-hex) to give the title compound as animpure brown oil (548 mg), which was used without further purification.

Step 2:(S)-5-(3-Fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid

A solution of (S)-methyl5-(3-fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate(548 mg from previous step) and KOH (876 mg, 15.6 mmol) in MeOH (6 mL)was stirred in a sealed tube at 70° C. for 17 h. The mixture wasacidified to pH 0 using 10% HCl, extracted with DCM (2×20 mL), dried(phase separator) and concentrated. The title compound was obtained asan impure brown oil (451 mg), which was used without furtherpurification.

Step 3:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

A stirred solution of(S)-5-(3-fluoro-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid (451 mg from previous step) and triethylamine (0.53 mL, 3.80 mmol)in dry DMF (12 mL) was treated with TFFH (451 mg, 1.71 mmol) at 0° C.under N₂. After stirring at r.t for 40 min, the mixture was cooled to 0°C. and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (240 mg, 2.05 mmol) wasadded. The mixture was stirred at r.t for 18 h before being diluted withMeOH (15 mL) and treated with HCl (4 M in dioxane, 6 mL). After 1.5 h atr.t., the reaction mixture was diluted with EtOAc (30 mL) and washedwith H₂O (2×20 mL). The combined aqueous washes were extracted withEtOAc (2×20 mL); the combined organic layers were washed with H₂O (20mL), dried (phase separator) and concentrated. LCMS analysis showedtarget material remained in the aqueous washes, which were thereforetreated with brine (30 mL) and extracted with EtOAc (3×20 mL). LCMSanalysis of the aqueous layer showed no target material now remained.The organic extracts were dried (phase separator), concentrated andcombined with the earlier organic residue. This mixture was purified bypreparative HPLC to give the title compound (140 mg) as a white solid.LCMS (ES+) 373 (M+H)⁺, RT 9.75 min (Analytical method 3); ¹H NMR δ(ppm)(400 MHz, DMSO-d₆): 10.30 (1H, s), 8.85 (1H, s), 7.50 (1H, d, J=2.1Hz), 7.23-7.12 (2H, m), 7.10-7.05 (1H, m), 6.75 (1H, d, J=2.1 Hz), 4.12(3H, s), 3.79 (2H, d, J=16.0 Hz), 3.41 (1H, d, J=16.6 Hz), 3.21 (1H, d,J=15.5 Hz), 2.18 (3H, d, J=2.7 Hz).

Example 69:(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Prepared following the same method as for Example 68 starting fromIntermediate 16. Preparative HPLC gave the title compound as a whitesolid (133 mg). LCMS (ES+) 373 (M+H)⁺, RT 9.55 min (Analytical method2); ¹H NMR δ (ppm)(400 MHz, DMSO-d₆): 10.30 (1H, s), 8.85 (1H, s), 7.50(1H, d, J=2.1 Hz), 7.23-7.12 (2H, m), 7.10-7.05 (1H, m), 6.75 (1H, d,J=2.1 Hz), 4.12 (3H, s), 3.79 (2H, d, J=16.0 Hz), 3.41 (1H, d, J=16.6Hz), 3.21 (1H, d, J=15.5 Hz), 2.18 (3H, d, J=2.7 Hz).

Example 70:(R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Prepared following the method described for Example 68 starting fromIntermediate 16. Preparative HPLC gave the title compound (54 mg). LCMS(ES+) 387 (M+H)⁺, RT 9.35 min (Analytical method 2); ¹H NMR δ(ppm)(DMSO-d₆): 10.27 (1H, s), 8.82 (1H, d, J=1.6 Hz), 7.22-7.04 (3H,m), 6.48-6.44 (1H, m), 3.83-3.61 (5H, m), 3.28 (1H, dd, J=4.9, 1.2 Hz),3.18 (1H, dd, J=13.5, 11.0 Hz), 2.49-2.14 (3H, m), 2.18-2.14 (3H, m).

Example 71:(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Step 1:(R)-5-(3-Fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5-((methylperoxy)methyl)-5,6-dihydro-4H-cyclopenta[d]thiazole

To a solution of Intermediate 15 (500 mg, 1.52 mmol) in ethanol (5 mL)was added 5-fluoropyridine-2-carbothioamide (356 mg, 2.28 mmol). Thereaction mixture was heated to 110° C. under microwave conditions for 1h. The reaction mixture was concentrated to give a dark red gum. Thecrude reaction material was purified by flash silica chromatography(gradient elution i-hex to 40% EtOAc in i-hex) to give the titlecompound as a bright orange gum (200 mg, 34%). Progressed withoutfurther purification.

Step 2:(R)-5-(3-Fluoro-2-methylphenyl)-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid

(R)-5-(3-fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5-((methylperoxy)methyl)-5,6-dihydro-4H-cyclopenta[d]thiazole(160 mg, 0.41 mmol), methanol (5 mL) and 15% aq. NaOH solution (1.10 mL,4.1 mmol) were combined in a sealed tube and heated to 65° C. for 18 h.The orange reaction mixture was evaporated in vacuo then diluted withEtOAc and H₂O. The aqueous layer was adjusted to pH 7 with 1 M HCl andthe layers separated. The organic layer was dried (MgSO₄) and evaporatedin vacuo. The residue was purified by flash silica chromatography(gradient elution i-hex to 100% EtOAc in i-hex) to give the titlecompound as an orange solid (85 mg, 53%). ¹H NMR δ (ppm)(CH₃OH-d₄): 8.26(1H, dd, J=20.1, 2.9 Hz), 8.04 (1H, dd, J=20.1, 8.8 Hz), 7.46 (1H, dt,J=8.8, 3.0 Hz), 7.18-7.13 (2H, m), 7.01-6.94 (1H, m), 3.95-3.82 (5H, m),3.53-3.42 (1H, m), 3.35 (1H, d, J=7.7 Hz), 2.27 (3H, d, J=2.7 Hz). AcidOH not seen Used crude without further purification.

Step 3:(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

A stirred solution of(R)-5-(3-Fluoro-2-methylphenyl)-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid (82 mg, 0.21 mmol) and triethylamine (0.096 mL, 0.68 mmol) in dryDMF (2 mL) was treated with TFFH (81 mg, 0.31 mmol) at 0° C. under N₂.After stirring at r.t. for 40 min, the mixture was cooled to 0° C. andO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (43 mg, 0.37 mmol) was added.The mixture was stirred at r.t. for 18 h before being diluted with MeOH(2 mL) and treated with HCl (4 M in dioxane, 1 mL). After 1.5 h at rt,the reaction mixture was diluted with EtOAc (10 mL) and washed with H₂O(2×10 mL). The combined aqueous washes were extracted with EtOAc (2×10mL); the combined organic layers were washed with H₂O (20 mL), dried(phase separator) and concentrated. Preparative HPLC gave the titlecompound as an off-white solid (36 mg). LCMS (ES+) 400 (M+H)⁺, RT 3.51min (Analytical method 1). ¹H NMR δ (ppm)(DMSO-d₆): 10.26 (1H, s), 8.82(1H, s), 8.30 (1H, dd, J=2.9, 0.6 Hz), 7.97 (1H, dd, J=8.8, 0.6 Hz),7.50 (1H, dd, J=8.8, 2.9 Hz), 7.21-7.03 (3H, m), 3.87 (3H, s), 3.73 (2H,t, J=15.6 Hz), 3.34 (1H, d, J=13.7 Hz), 3.18 (1H, d, J=15.6 Hz),2.18-2.14 (3H, m).

Example 72:(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

Step 1: (S)-Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate

A suspension of intermediate 10 (0.114 g, 0.31 mmol), cyclopropylboronic acid (0.029 g, 0.34 mmol), palladiumtetrakis(triphenylphosphine) (0.015 g) and cesium carbonate (0.5 g, 1.54mmol) in a mixture of degassed dioxane/water (9:1, 10 mL) was stirred at110° C. for 16 h. The reaction was cooled to r.t., diluted with EtOAc(75 mL) and subjected to an aqueous workup. The organic layer wasconcentrated under vacuum to give the title compound as an impure yellowoil, which was used without further purification in the next step. LCMS(ES+) 332 (M+H)⁺.

Step 2:(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylicacid

(S)-Methyl2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylate(26 mg, 0.07 mmol), MeOH (2 mL) and 15% aq. NaOH soln. (0.5 mL) werecombined in a sealed tube and heated to 70° C. for 4 days. The reactionmixture was cooled and evaporated to dryness. Residue was partitionedbetween 1N HCl and EtOAc. Organics were dried (MgSO₄) and evaporated todryness to give the title compound as an off white solid. LCMS (ES+) 318(M+H)⁺.

Step 3:(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxylicacid (53 mg, 0.16 mmol), TFFH (49 mg, 0.18 mmol), DMF (2 mL) andtriethylamine (0.12 mL) were combined and stirred for 1 h.O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (22 mg, 0.184 mmol) was thenadded and stirring continued for 1 day. Volatile solvents were removedin vacuo. MeOH (1 mL) and 2N HCl in Et₂O (1 mL) were added and reactionmixture was stirred for 30 min. Volatile solvents were removed in vacuoand remaining crude material was purified by preparative HPLC to give(S)-2-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide(1 mg). LCMS (ES+) 333 (M+H)⁺, 331 (M−H)⁻, RT 9.68 min (Analyticalmethod 2); ¹H NMR (400 MHz, CHCl₃-d) 8.19 (1H, s) 7.03-6.86 (3H, m),3.85-3.70 (1H, m) 3.05-2.95 (1H, m) 2.92-2.75 (1H, m) 2.50-2.38 (1H, m),2.41-2.17 (4H, m) 1.20-0.90 (4H, m). OH resonance not observed.

Example 73:(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

Prepared following the method described for Example 72. Preparative HPLCgave the title compound as an off-white solid (4 mg). LCMS (ES+) 383(M+H)⁺, RT 11.0 min. (Analytical method 2); ¹H NMR δ (ppm)(400 MHz,DMSO-d₆): 10.55 (1H, s), 8.92 (1H, s), 7.76 (1H, d, J=7.4 Hz), 7.40-7.34(3H, m), 7.21-7.09 (2H, m), 7.02 (1H, dd, J=7.8, 7.8 Hz), 3.77-3.60 (1H,m), 3.06-2.83 (2H, m), 2.59 (3H, s), 2.43-2.31 (1H, m), 2.17 (3H, d,J=2.4 Hz).

Examples 74 and 75:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideandE2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Step 1: Methyl5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

A suspension of 4-fluoro-2-methylphenylboronic acid (105 mg, 0.68 mmol),Intermediate 12 (188 mg, 0.51 mmol),tetrakis(triphenylphosphine)palladium(0) (93 mg, 80 μmol) and CsF (100mg, 0.66 mmol) in DME (3 mL) and MeOH (0.75 mL) was purged with N₂ andstirred in a microwave reactor at 120° C. for 10 min. The mixture wasconcentrated and purified by flash silica chromatography (gradientelution of 0% to 100% EtOAc in i-hex) to give the title compound (79 mg)in 75% purity as a colorless oil, which was used without furtherpurification.

Step 2:5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid

To a solution of methyl5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate(79 mg mixture from previous step) in methanol (2 mL) was added KOH (122mg). The reaction mixture was capped and heated at 70° C. for 20 h.After this time the contents were cooled to r.t. and acidified to pH 0with 10% HCl. The mixture was extracted with DCM (2×20 mL), dried (phaseseparation cartridge) and concentrated to give the title compound (58mg) in 85% purity as a brown oil, which was used without furtherpurification.

Step 3:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideandE2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

A stirred solution of5-(3-fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylicacid (58 mg, mixture from the previous step) in DCM (1 mL) at 20° C. wastreated sequentially with oxalyl chloride (14 μL) and DMF (10 μL). Themixture was stirred for 25 min until gas evolution ceased. MeCN (1 mL)and hydroxylamine (28 μL) were added and the mixture heated to 100° C.in a microwave reactor for 10 min. Purification by preparative HPLC andchiral preparative HPLC gave the E1-(abs) and E2-(abs) enantiomers (1 mgand 2 mg respectively) which were arbitrarily assigned. (Chiralpak IA50/50 EtOH (0.1% formic acid)/Heptane, 1.0 mL/min, r.t., RT 11.3 min(E2-(abs)) and 6.1 min (E1-(abs)). E2-(abs): LCMS (ES+) 401 (M+H)⁺, RT4.06 min (Analytical method 1); ¹H NMR δ (ppm)(400 MHz, DMSO-d₆): 10.31(1H, s), 8.82 (1H, s), 7.76-7.71 (1H, m), 7.25 (1H, dd, J=2.4, 10.0 Hz),7.20-7.05 (4H, m), 3.90-3.76 (2H, m), 3.40-3.31 (1H, m), 3.26-3.17 (1H,m), 2.56 (3H, s), 2.21-2.18 (3H, m). E1-(abs): LCMS (ES+) 401 (M+H)⁺, RT4.06 min (Analytical method 1); ¹H NMR δ (ppm)(400 MHz, DMSO-d₆): 10.31(1H, s), 8.82 (1H, s), 7.76-7.71 (1H, m), 7.25 (1H, dd, J=2.4, 10.0 Hz),7.20-7.05 (4H, m), 3.90-3.76 (2H, m), 3.40-3.31 (1H, m), 3.26-3.17 (1H,m), 2.56 (3H, s), 2.21-2.18 (3H, m).

Example 76 and 77:E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideandE2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

Prepared following the same method as for Example 74 and 75.Purification by preparative HPLC and chiral HPLC gave the E1-(abs) andE2-(abs) enantiomers (3 mg and 5 mg respectively) which were arbitrarilyassigned. (Chiralpak IC 50/50 EtOH (0.1% formic acid)/heptane, 1.0mL/min, RT 6.1 min (E1-(abs)) and 11.6 min (E2-(abs)). E1-(abs)Enantiomer: LCMS (ES+) 387 (M+H)⁺, RT 3.15 min (Analytical method 1); ¹HNMR δ (ppm)(400 MHz, DMSO-d₆): 10.28 (1H, s), 8.82 (1H, s), 7.74 (1H,s), 7.19-7.05 (3H, m), 3.78 (3H, s), 3.77-3.67 (2H, m), 3.14 (1H, d,J=15.8 Hz), 2.53 (3H, s), 2.21-2.16 (3H, m), 1H obscured by water.E2-(abs) Enantiomer: LCMS (ES+) 387 (M+H)⁺, RT 3.16 min (Analyticalmethod 1); ¹H NMR δ (ppm)(400 MHz, DMSO-d₆): 10.28 (1H, s), 8.82 (1H,s), 7.74 (1H, s), 7.19-7.05 (3H, m), 3.78 (3H, s), 3.77-3.67 (2H, m),3.14 (1H, d, J=15.8 Hz), 2.53 (3H, s), 2.21-2.16 (3H, m), 1H obscured bywater resonance.

Example 78:(S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide

Prepared following the same method as for Example 72. Preparative HPLCgave the title compound as a white solid (8 mg). LCMS (ES+) 387 (M+H)⁺,RT 3.8 min (Analytical method 1); ¹H NMR δ (ppm)(400 MHz, DMSO-d₆):10.57 (1H, d, J=1.4 Hz), 8.93-8.91 (1H, m), 8.02-7.97 (2H, m), 7.38-7.33(2H, m), 7.21-7.09 (2H, m), 6.98 (1H, d, J=7.5 Hz), 3.73-3.65 (1H, m),3.02-2.94 (1H, m), 2.91-2.82 (1H, m), 2.40-2.32 (1H, m), 2.16 (3H, d,J=2.4 Hz) (data reported for major rotamer).

Example 79:(R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Step 1: (R)-Methyl3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate

tBuOK (124 mg, 1.1 mmol) and THF (6 mL) were combined under a nitrogenatmosphere. The reaction mixture was cooled with an ice bath and ethylformate (0.24 mL, 4 mmol) was added drop-wise. After 15 min Intermediate2 (250 mg, 1 mmol) was added drop-wise as a solution in ethyl formate (2mL). The reaction mixture was stirred for a further 1 h with ice bathcooling then diluted with EtOAc, washed with 1N HCl, then brine, dried(phase separator) and evaporated to dryness to give the crude aldehydeas a pale brown oil. The crude residue was dissolved in anhydrous THF (6mL) and dimethylamine (2 mL, 4 mmol, 2 M in THF) added. The reactionmixture was then stirred for a further 36 h. After this time thereaction mixture was concentrated under reduced pressure and purified byflash silica column chromatography (gradient elution i-hex to 66% EtOAcin i-hex) to give the title compound as a pale yellow solid (0.25 g, 83%over 2 steps). LCMS (ES+) 306 (M+H)⁺.

Step 2: (R)-Methyl1-(3-fluoro-2-methylphenyl)-3-(4-fluorobenzylidene)-4-oxocyclopentanecarboxylate

(R)-Methyl3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate(250 mg, 0.8 mmol) and THF (5 mL) were combined under a nitrogenatmosphere. The reaction mixture was cooled with an ice bath and4-fluorophenyl magnesium bromide (2 mL, 2 mmol, 1 M in THF) was addeddrop-wise. The reaction mixture was stirred for 1 h with ice bathcooling then quenched with aq. NH₄Cl (2 mL). The solution was thendiluted with EtOAc, washed with water, then brine, dried (phaseseparator) and evaporated to dryness and purified by flash silica columnchromatography (gradient elution i-hex to 20% EtOAc in i-hex) to givethe title compound as a colorless solid (0.28 g, 95%). LCMS (ES+) 357(M+H)⁺.

Step 3: (5R)-Methyl5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,3,3a,4,5,6-hexahydrocyclopenta[c]pyrazole-5-carboxylate

(R)-Methyl1-(3-fluoro-2-methylphenyl)-3-(4-fluorobenzylidene)-4-oxocyclopentanecarboxylate(130 mg, 0.4 mmol), indium chloride (20 mg, 0.15 mmol), methylhydrazine(25 μL, 0.44 mmol) and ethanol (6 mL) were combined under a nitrogenatmosphere. The reaction mixture was then refluxed for 2 h. After thistime the reaction mixture was cooled to room temperature and passedthrough a pad of silica gel eluting with 50% EtOAc in i-hex to givecrude hydrazide as a 3:1 mixture of syn/anti isomers. LCMS (ES+) 385(M+H)⁺.

Step 4: (R)-Methyl5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate

(5R)-Methyl5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,3,3a,4,5,6-hexahydrocyclopenta[c]pyrazole-5-carboxylate (80 mg, 0.2 mmol), DDQ (52 mg, 0.23mmol) and anhydrous dioxane (3 mL) were combined under a nitrogenatmosphere. The reaction mixture was then refluxed for 2 h. After thistime the reaction mixture was cooled to r.t., concentrated under reducedpressure and purified by flash silica column chromatography (gradientelution i-hex to 60% EtOAc in i-hex) to give the title compound as apale yellow oil (53 mg, 66%). LCMS (ES+) 383 (M+H)⁺.

Step 5:(R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylicacid

To a solution of (R)-methyl5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate(52 mg, 0.14 mmol) in THF/methanol/water (1:1:0.5, 2.5 mL) was addedlithium hydroxide hydrate (0.03 g, 0.70 mmol). The reaction mixture wascapped and heated at 65° C. for 18 h. After this time the contents werecooled to r.t. and methanol was removed under reduced pressure. Aqueousresidues were partitioned between EtOAc (15 mL) and 1 M aqueous HCl (15mL). Organic layers were extracted, washed with brine (20 mL), dried,filtered (phase separation cartridge) and concentrated to give the titlecompound as a pale yellow oil which was used directly (42 mg, 84%).

Step 6:(R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

To a solution of(R)-5-(3-fluoro-2-methylphenyl)-3-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylicacid (0.40 g, 1.1 mmol), and triethylamine (0.33 g, 468 μL, 3.3 mmol) inanhydrous DMF (10 mL) was added TFFH (0.36 g, 1.42 mmol) at 0° C. Thereaction mixture was stirred at this temperature for 15 min, thenO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.2 g, 1.67 mmol) was addedin a single portion. The reaction mixture was then stirred at r.t. for24 h. After this time the reaction mixture was quenched by the additionof 1 M HCl solution (5 mL). The reaction was partitioned between EtOAc(30 mL) and 1 M HCl (15 mL). The organic layer was separated, washedwith brine (40 mL), dried, filtered (phase separation cartridge) andconcentrated to give the crude THP protected hydroxamic acid as a paleyellow oil. To this oil was added anhydrous methanol (3 mL) and 4 M HClin dioxane (2 mL). The reaction mixture was stirred at r.t. for 30 min.After this time solvents were removed under reduced pressure to givecrude hydroxamic acid which was purified by preparative HPLC to give thetitle compound as a colorless solid (20 mg). LCMS (ES+) 384 (M+H)⁺, RT3.43 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.19 (1H, s),8.76 (1H, s), 7.58-7.53 (2H, m), 7.38-7.32 (2H, m), 7.14 (1H, t, J=7.3Hz), 7.04 (2H, t, J=7.8 Hz), 3.78 (3H, s), 3.64-3.53 (2H, m), 3.02 (1H,d, J=7.2 Hz), 2.98 (1H, d, J=7.6 Hz), 2.16 (3H, d, J=2.7 Hz).

Examples 80 and 81:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamideandE2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide

Step 1: 5-Phenyl-1,3,4-oxathiazol-2-one

To a stirred solution of amide (24.8 mmol) in THF (50 mL) was addedchlorocarbonylsulfenyl chloride (29.8 mmol). The solution was stirred atr.t for 17 h, concentrated in vacuo. Purification by flashchromatography (5% EtOAc in i-hex) gave the title compound as anoff-white solid (3.9 g, 88%). LCMS (ES+) 180 (M+H)⁺

Step 2: Dimethyl 3-phenylisothiazole-4,5-dicarboxylate

A solution of 5-phenyl-1,3,4-oxathiazol-2-one (12.7 mmol) and dimethylacetylenedicarboxylate (38.1 mmol) in CHCl₃ (10 mL) was heated in themicrowave at 160° C. for 1 h, or until evolution of gas stopped. Themixture was then concentrated and purified by flash chromatography (5%EtOAc in i-hex) to give the title compound as a colorless oil (3.09 g,88%). LCMS (ES+) 278 (M+H)⁺

Step 3: (3-Phenylisothiazole-4,5-diyl)dimethanol

To a cooled solution of dimethyl 3-phenylisothiazole-4,5-dicarboxylate(10.7 mmol) in THF (180 mL) was added Super-Hydride (53.3 mmol) over a10 min period and the reaction then stirred at r.t for 1.5 h. Themixture was quenched with 1M HCl (70 mL), the volume reduced to half andextracted into EtOAc. The aqueous was re-extracted with further portionsof EtOAc and the organics combined, dried (MgSO₄), filtered andconcentrated. Purification by flash chromatography (5% to 15% MeOH inDCM gradient) gave the title compound as a colorless oil (2.36 g, >99%).LCMS (ES+) 222 (M+H)⁺

Step 4: 4,5-Bis(bromomethyl)-3-phenylisothiazole

To a stirred solution of (3-phenylisothiazole-4,5-diyl)dimethanol (13.6mmol) in DCM/Et₂O (1:1, 100 mL) was added phosphorous tribromide (27.2mmol) dropwise. The mixture was heated to 30° C. for 3 h. The mixturewas diluted with H₂O (50 mL) and the volatiles concentrated beforeextraction with DCM (2×50 mL). The combined organics were passed througha phase separator and concentrated. Purification by flash chromatography(5% EtOAc in i-hex) gave the title compound as a colorless oil (3.02 g,64%). LCMS (ES+) 348 (M+H)⁺

Step 5: Methyl5-(3-fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylate

To a stirred solution of methyl 2-(3-fluoro-2-methylphenyl)acetate (5.4mmol) in DMF (200 mL) was added NaH (5.4 mmol). This was stirred for 1 hwith occasional heating until no more H₂ gas evolution was observed.This solution was then added slowly dropwise to a stirred solution of4,5-bis(bromomethyl)-3-phenylisothiazole (4.9 mmol) in DMF (200 mL) at0° C. A further portion of NaH (5.4 mmol) was added and the reactionmixture heated to 60° C. for 1 h. An additional portion of NaH (5.4mmol) was added and stirring continued for 1 h. The reaction wasquenched with H₂O (in ice-bath) and the volatiles removed under reducedpressure. The remaining residue was partitioned between EtOAc and H₂O.The organics were collected, dried (MgSO₄), filtered and concentrated.Purification by flash chromatography (3% to 5% EtOAc in i-hex) gave thetitle compound (125 mg, 7%). LCMS (ES+) 367 (M+H)⁺

Step 6:5-(3-Fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylicacid

To a solution of methyl5-(3-fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylate(97 mg, 0.26 mmol) in THF/methanol (1:1, 2 mL) was added sodiumhydroxide (2.0 mL, 2 M aqueous solution). The reaction mixture wascapped and heated at 70° C. for 18 h. After this time the contents werecooled to r.t. and methanol was removed under reduced pressure. Aqueousresidues were partitioned between EtOAc (15 mL) and 1 M aqueous HCl (15mL). Organic layers were extracted, washed with brine (20 mL), dried,filtered (phase separation cartridge) and concentrated to give the titlecompound as a colorless oil which was used directly in the next step (60mg, 65%).

Step 7:E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamideandE2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide

To a solution of5-(3-fluoro-2-methylphenyl)-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxylicacid (60 mg from previous step), triethylamine (92 μl, 0.65 mmol) inanhydrous DMF (1 mL) was added TFFH (49 mg, 0.19 mmol) at 0° C. Thereaction mixture was stirred at this temperature for 15 min, thenO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (39 mg, 0.34 mmol) was addedin a single portion. Reaction mixture was then stirred at r.t. for 24 h.After this time the reaction mixture was quenched by the addition of 1 MHCl solution (2 mL). The reaction was partitioned between EtOAc (5 mL)and 1 M HCl (5 mL). The organic layer was separated, washed with brine(10 mL), dried, filtered (phase separation cartridge) and concentratedto give the crude THP protected hydroxamic acid as a pale yellow oil. Tothis oil was added anhydrous methanol (2 mL) and 4 M HCl in dioxane (1mL). The reaction mixture was stirred at r.t. for 30 min. After thistime solvents were removed under reduced pressure to give crudehydroxamic acid which was purified by preparative HPLC and chiral HPLCto give the E1-(abs) and E2-(abs) enantiomers (2 mg and 3 mgrespectively) which were arbitrarily assigned. (Chiralpak IC 40/60IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 13.2 min(E1-(abs)) and 4.9 min (E2-(abs)). E1-(abs) LCMS (ES+) 369 (M+H)⁺, RT3.77 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.3 (1H, s),8.84 (1H, s), 7.90-7.85 (2H, m), 7.55-7.40 (3H, m), 7.20-7.00 (3H, m),3.95 (1H, d, J=15.2 Hz), 3.92 (1H, d, J=17.2 Hz), 3.45 (1H, d, J=17.2Hz), 3.42 (1H, d, J=15.2 Hz), 2.17 (3H, d, J=2.4 Hz). E2-(abs) LCMS(ES+) 369 (M+H)⁺, RT 3.77 min (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 10.3 (1H, s), 8.84 (1H, s), 7.90-7.85 (2H, m), 7.55-7.40(3H, m), 7.20-7.00 (3H, m), 3.95 (1H, d, J=15.2 Hz), 3.92 (1H, d, J=17.2Hz), 3.45 (1H, d, J=17.2 Hz), 3.42 (1H, d, J=15.2 Hz), 2.17 (3H, d,J=2.4 Hz).

Example 82:2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide

Step 1: 2-(3-Fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carbonitrile

To a solution of 2-(3-fluoro-2-methylphenyl)acetonitrile (0.298 g, 2.0mmol) in DMF (30 mL) was added NaH (0.176 g, 4.4 mmol) stirred at RTunder N₂ for 30 min, α,α′-dibromo-o-xylene (0.58 g, 2.2 mmol) added andthe reaction mixture was stirred at RT under N₂ for 92 h. SaturatedNH₄Cl solution (30 mL) added extracted with EtOAc (3×30 mL). Combinedorganics were extracted with brine (20 mL). EtOAc layers were thendried, filtered (phase separation cartridge) and concentrated ontosilica and purified by flash silica column chromatography (gradientelution i-hex to 100% EtOAc in i-hex) to yield the title compound as apale yellow oil (0.098 g, 19%). LCMS (ES+) 252 (M+H)⁺

Step 2: 2-(3-Fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carboxylicacid

2-(3-Fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carbonitrile (98 mg,0.39 mmol) was dissolved in dioxane (2 mL) and 4M HCl in dioxane (1 mL)was added. The mixture was stirred at 120° C. for 96 h to give the titlecompound as a white solid (63 mg, 97%) and used crude in next step. LCMS(ES+) 271 (M+H)⁺.

Step 3:2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide

To a solution of2-(3-fluoro-2-methylphenyl)-2,3-dihydro-1H-indene-2-carboxylic acid (63mg from previous step) and triethylamine (92 μl, 0.65 mmol) in anhydrousDMF (1 mL) was added TFFH (49 mg, 0.19 mmol) at 0° C. The reactionmixture was stirred at this temperature for 15 min, thenO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (39 mg, 0.34 mmol) was addedin a single portion. The reaction mixture was then stirred at r.t. for24 h. After this time the reaction mixture was quenched by the additionof 1 M HCl solution (2 mL). The reaction was partitioned between EtOAc(5 mL) and 1 M HCl (5 mL). The organic layer was separated, washed withbrine (10 mL), dried, filtered (phase separation cartridge) andconcentrated to give the crude THP protected hydroxamic acid as a paleyellow oil. To this oil was added anhydrous methanol (2 mL) and 4 M HClin dioxane (1 mL). The reaction mixture was stirred at r.t. for 30 min.After this time solvents were removed under reduced pressure to givecrude hydroxamic acid which was purified by preparative HPLC to give thetitle compound as a colorless solid (20 mg). LCMS (ES+) 285 (M+H)⁺, RT3.58 min (Analytical method 1). ¹H NMR δ (ppm)(DMSO-d₆): 10.19 (1H, s),8.74 (1H, s), 7.30-7.15 (2H, m), 7.15-6.95 (5H, m), 3.71 (2H, d, J=16.8Hz), 3.20 (2H, d, J=16.8 Hz), 2.17 (3H, d, J=2.4 Hz).

Example 83:2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxamide

Step 1: Methyl2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate

Cyclopropanecarboximidamide hydrochloride (0.27 g, 2.2 mmol) was addedto a solution of intermediate 9 (0.77 g, 2.2 mmol) in dry methanol (15mL). Sodium methoxide (0.24 g, 4.44 mmol) was added and the reactionmixture heated at reflux for 3.25 h. Additionalcyclopropanecarboximidamide hydrochloride (0.10 g, 0.83 mmol), sodiummethoxide (0.10 g, 1.85 mmol) and methanol (3 mL) were added and thereaction heated at reflux for 3 h. Additionalcyclopropanecarboximidamide hydrochloride (0.05 g, 0.41 mmol), sodiummethoxide (0.06 g, 1.11 mmol) and methanol (10 mL) were added and thereaction stirred at room temperature. After 18 h the reaction mixturewas quenched with saturated ammonium chloride solution. The reactionmixture was concentrated to a ¼ volume, diluted with DCM and water andtransferred to a separating funnel. The mixture was extracted with DCM(×3), dried (phase separating cartridge) and evaporated to dryness. Thecrude mixture was purified by silica gel column chromatography (25 gSNAP column), eluting with 0-70% EtOAc in i-hex to afford the titlecompound as a solid (0.44 g, 54%). ¹H NMR δ (ppm)(CHCl₃-d): 12.32 (1H,br. s), 7.23-7.14 (2H, m), 7.04-6.95 (1H, m), 3.71 (3H, s), 3.02 (1H,dd, J=17.2, 10.3 Hz), 2.88-2.67 (3H, m), 2.64-2.53 (2H, m), 2.33-2.21(2H, m), 2.16 (3H, d, J=3.1 Hz), 1.87-1.79 (1H, m), 1.20-1.14 (2H, m),1.08-1.01 (2H, m).

Step 2: Methyl2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-(((trifluoromethyl)sulfinyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate

Methyl2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate(0.44 g, 1.19 mmol) was dissolved in DCM (15 mL) and cooled to 0° C.Pyridine (0.15 mL, 1.79 mmol) was added followed by dropwise addition oftriflic anhydride (0.24 mL, 1.42 mmol). The reaction mixture was stirredat 0° C. for 2 h. The reaction mixture was transferred to a separatingfunnel with DCM and washed with water. The combined organic extractswere dried (phase separating cartridge), and concentrated under reducedpressure. Purified by silica gel column chromatography eluting with0-100% EtOAc in i-hex to afford the title compound as a yellow oil (153mg, 26%). ¹H NMR δ (ppm)(CHCl₃-d): 7.23-7.12 (2H, m), 7.05-6.97 (1H, m),3.75 (3H, s), 3.33 (1H, dd, J=16.6, 10.8 Hz), 3.09-2.97 (2H, m),2.92-2.83 (1H, m), 2.71-2.62 (2H, m), 2.29-2.10 (5H, m), 1.17-1.06 (4H,m).

Step 3: Methyl2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate

Palladium on carbon (100 mg), triethylamine (0.06 mL, 0.43 mmol) and 3 Åmolecular sieves were added to methyl2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-4-(((trifluoromethyl)sulfinyl)oxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate(153 mg, 0.30 mmol) in EtOAc (10 mL) at room temperature. The reactionmixture was placed under an atmosphere of hydrogen and stirred at roomtemperature for 21 h. The reaction mixture was filtered over celitewashing with EtOAc and methanol. The filtrate was condensed and theresultant oil partitioned between water and DCM. The mixture wasextracted with DCM (×2) and the combined organic extracts dried (phaseseparating cartridge) and evaporated to dryness to afford the titlecompound as a yellow oil (120 mg, >100%). Used without furtherpurification in the next step.

Step 4:2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylicacid

Methyl2-cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylate(0.30 mmol), lithium hydroxide (100 mg), THF (2 mL), MeOH (2 mL) andwater (1 mL) were combined in a sealed tube at 65° C. for 15 h.Additional LiOH (50 mg) was added and heated for a further 21 h. Thereaction mixture was cooled to room temperature and partiallyconcentrated under reduced pressure. Water was added and the aqueousmixture acidified with 1N hydrochloric acid. The resultant whiteprecipitate was collected by filtration and dried. There was evidence ofthe target material in the filtrate. This was condensed, extracted withDCM (×3), dried (phase separating cartridge) and evaporated to dryness.This was combined with the filtered solid and used without furtherpurification in the next step (58 mg, 57%).

Step 5:2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxamide

2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxylicacid (58 mg, 0.17 mmol), TFFH (68 mg, 0.26 mmol), DMF (1.5 ml) andTriethylamine (47 μl) were combined and stirred at 0° C. for 0.5 h.Triethylamine (59 μl, 0.43 mmol) and hydroxylamine hydrochloride (24 mg,0.34 mmol) were added and the reaction stirred at room temperature for20 h. The reaction mixture was diluted with water (2-3 drops), filteredand purified by preparative HPLC to afford the title compound as a whitesolid (5 mg). LCMS (ES+) 356 (M+H)⁺, RT 3.04 min (Analytical method 1);¹H NMR δ (ppm)(CH₃OH-d₄): 8.27 (1H, s), 7.20-7.18 (1H, m), 7.17-7.07(1H, m), 6.96-6.87 (1H, m), 3.40-3.31 (1H, m), 3.12-2.99 (1H, m), 2.86(1H, dd, J=16.7, 8.7 Hz), 2.79-2.66 (1H, m), 2.60-2.47 (2H, m),2.22-2.01 (6H, m), 1.08-1.00 (4H, m).

Examples 84 and 85:E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamideandE2-(abs)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide

Step 1: Methyl6-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate

2,2,2-Trifluoroethylhydrazine (0.32 mL, 70% aqueous solution) was addedto a solution of intermediate 9 (0.64 g, 1.8 mmol) in dry ethanol (7 mL)in a sealed tube and heated at 95° C. for 16 h. The reaction mixture wascooled to room temperature and concentrated under reduced pressure. Theresultant gum was allowed to stand at room temperature. Partialcrystallization occurred over 2 weeks. The solid was trituratedsequentially with EtOAc then 20% EtOAc in iso-hexane. The resultantsolid was collected by filtration, washing with 20% EtOAc in i-hexaneand dried in the vacuum oven to afford the title compound as anoff-white solid (360 mg, 50%). ¹H NMR δ (ppm)(DMSO-d₆): 10.55 (0.67H,s), 10.39 (0.33H, s), 7.35 (1H, d, J=8.08 Hz), 7.23 (1H, dd, J=14.82,7.41 Hz), 7.13-7.04 (1H, m), 4.62 (1.33H, dd, J=18.38, 9.19 Hz), 4.40(0.67H, d, J=10.33 Hz), 3.64 (3H, s), 2.72-2.58 (2H, m), 2.50-2.32 (4H,m), 2.25-2.12 (2H, m), 2.06 (3H, s). The NMR spectrum was consistentwith a mixture of tautomers.

Step 2: Methyl6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate

Methyl6-(3-fluoro-2-methylphenyl)-3-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate(0.36 g, 0.90 mmol) was dissolved in DCM (10 mL). Pyridine (0.11 mL,1.35 mmol) was added at room temperature followed by dropwise additionof a triflic anhydride (0.06 mL, 0.36 mmol) in DCM (1 mL). The reactionmixture was cooled to 0° C. and triflic anhydride (0.12 mL, 0.72 mmol)in DCM (3 mL) was added dropwise. After 1.5 h the reaction mixture wastransferred to a separating funnel with DCM and washed with water. Thecombined organic extracts were dried (phase separating cartridge) andevaporated to dryness. The crude material was purified by silica gelcolumn chromatography eluting with 0-70% EtOAc in i-hex to afford thetitle compound as a colorless gum (380 mg, 80%). ¹H NMR δ(ppm)(CHCl₃-d): 7.21-7.15 (2H, m), 7.03-6.95 (1H, m), 4.57 (2H, dd,J=16.20, 8.10 Hz), 3.70 (3H, s), 3.01-2.92 (1H, m), 2.84-2.72 (2H, m),2.66-2.49 (3H, m), 2.31-2.18 (2H, m), 2.15 (3H, d, J=3.13 Hz).

Step 3: Methyl6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate

Palladium on carbon (300 mg), triethylamine (0.14 mL, 1.00 mmol) and 3 Åmolecular sieves were added to methyl6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate(0.38 g, 0.70 mmol) in EtOAc (20 mL) at room temperature. The reactionmixture was placed under an atmosphere of hydrogen and stirred at roomtemperature for 20 h. The reaction mixture was filtered over celitewashing with methanol. The filtrate was condensed and the resultant oilpartitioned between water and DCM. The mixture was extracted with DCM(×2) and the combined organics dried (phase separating cartridge),filtered and evaporated to dryness to afford the title compound as ayellow oil (331 mg, >100%). Used without further purification in thenext step. ¹H NMR δ (ppm)(CHCl₃-d): 7.22-7.14 (3H, m), 7.02-6.95 (1H,m), 4.58 (2H, dd, J=16.98, 8.49 Hz), 3.72 (3H, s), 2.94-2.91 (1H, m),2.86-2.73 (2H, m), 2.67-2.56 (3H, m), 2.34-2.19 (2H, m), 2.18 (3H, d,J=3.13 Hz).

Step 4:6-(3-Fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylicacid

Methyl6-(3-fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylate(0.33 g, 0.86 mmol), lithium hydroxide (180 mg), THF (2 mL), MeOH (2 mL)and water (1 mL) were combined in a sealed tube at 65° C. for 18.5 h.Additional LiOH (135 mg) was added and heated for a further 54 h. Thereaction mixture was cooled to room temperature and evaporated todryness. The mixture was partitioned between water and DCM, acidified topH 1 using 2N hydrochloric acid. The mixture was extracted with DCM (3times), dried (phase separating cartridge) and evaporated to dryness toafford the title compound as a white solid (250 mg, 79%). ¹H NMR δ(ppm)(DMSO-d₆): 12.72 (1H, s), 7.50-7.46 (1H, m), 7.32 (1H, d, J=8.1Hz), 7.25-7.17 (1H, m), 7.11-7.04 (1H, m), 4.94 (2H, dd, J=18.4, 9.2Hz), 2.81 (1H, dd, J=16.2, 10.5 Hz), 2.71-2.58 (3H, m), 2.56-2.47 (2H,m), 2.48-2.37 (2H, m), 2.17 (3H, d, J=3.1 Hz).

Step 5:E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamideandE2-(abs)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide

6-(3-Fluoro-2-methylphenyl)-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxylicacid (210 mg, 0.57 mmol) was suspended in dry DCM (4 mL). Oxalylchloride (53 μL, 0.62 mmol) and DMF (1 drop) were added with stirring atroom temperature. After 2 h MeCN (4 mL) was added and the reactiontransferred to a 20 mL microwave tube. Hydroxylamine (200 μL, 50%aqueous solution) was added and the reaction heated in the microwave at100° C. for 10 min. The reaction is evaporated to dryness and suspendedin methanol. The slurry was triturated with water to afford a whitepowder which was purified by silica gel column chromatography (gradientelution 0-5% MeOH in DCM). Chiral preparative HPLC gave the E1-(abs)-and E2-(abs)-enantiomers which were arbitrarily assigned. (Chiralpak IA,Method 40/60 EtOH (0.1% formic acid)/Heptane 1.0 mL/min, RT 6.3(E1-(abs)) and 17.3 min (E2-(abs)). E1-(abs)-enantiomer was obtained asa cream solid (34 mg). LCMS (ES+) 386 (M+H)⁺, RT 9.85 (Analytical method2). ¹H NMR δ (ppm)(DMSO-d₆): 10.11 (1H, s), 8.68 (1H, s), 7.44 (1H, s),7.36-7.30 (1H, m), 7.20 (1H, q, J=7.40 Hz), 7.10-7.03 (1H, m), 4.92 (2H,q, J=9.18 Hz), 2.82 (1H, dd, J=15.69, 10.24 Hz), 2.70-2.39 (7H, m), 2.13(3H, d, J=2.8 Hz). E2-(abs)-enantiomer was obtained as a white solid (31mg). LCMS (ES+) 386 (M+H)⁺, RT 3.36 min (Analytical method 1). ¹H NMR δ(ppm)(DMSO-d₆): 10.11 (1H, s), 8.68 (1H, s), 7.44 (1H, s), 7.32 (1H, d,J=8.1 Hz), 7.20 (1H, dd, J=14.8, 7.4 Hz), 7.10-7.03 (1H, m), 4.92 (2H,dd, J=18.4, 9.2 Hz), 2.82 (1H, dd, J=15.7, 10.2 Hz), 2.70-2.41 (7H, m),2.13 (3H, d, J=3.2 Hz).

Example 86:N-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide

The title compound was prepared according to Example 83 and 84, usingthe TFFH method of hydroxamic acid formation as in Step 5 of Example 82.Preparative HPLC gave the title compound as a white solid (38 mg). LCMS(ES+) 354 (M+H)⁺, RT 9.44 min (Analytical method 2); ¹H NMR δ(ppm)(DMSO-d₆): 10.46 (1H, s), 8.75 (1H, s), 7.46 (1H, s), 7.39-7.28(4H, m), 7.25-7.18 (1H, m), 4.92 (2H, dd, J=18.4, 9.2 Hz), 2.78 (1H, dd,J=15.8, 10.8 Hz), 2.72-2.55 (3H, m), 2.48-2.39 (2H, m), 2.02-1.87 (2H,m).

Examples 87 and 88:E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide andE2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide

To a solution of methyl 2,3-dihydro-1H-indene-1-carboxylate (545 mg,3.10 mmol) in toluene (3.8 mL) was added dicyclohexylamine (632 μL, 3.17mmol) followed by BuLi (2 mL, 3.2 mmol, 1.6 M in hexane). In a seperateflask, Pd(OAc)₂ (8 mg, 0.037 mmol), P(tBu)₃. HBF₄ (24 mg, 0.084 mmol),bromobenzene (163 μL, 1.55 mmol) and toluene (2 mL) were combinedsequentially and heated to 100° C. for 1 min. The enolate solution wasthen added to the reaction mixture via syringe. The combined mixture washeated at 100° C. for 1 h. The mixture was left to cool to r.t., thenwater (8 mL) and DCM (20 mL) added and the biphasic mixture passedthrough a phase separator. The organics were concentrated and purifiedby silica gel column chromatography (10% EtOAc in i-hex), to give thetitle compound as a yellow oil (277 mg, 77%). LCMS (ES+) 253 (M+H)⁺.

Step 2: 1-Phenyl-2,3-dihydro-1H-indene-1-carboxylic acid

To a stirred suspension of tBuOK (813 mg, 7.25 mmol) in dry ether (14mL) at 0° C., was added H₂O (33.5 μL, 1.86 mmol). To this was addedmethyl 1-phenyl-2,3-dihydro-1H-indene-1-carboxylate (211 mg, 0.84 mmol)and the reaction mixture was left to warm to r.t and stirred for 96 h.The mixture was cooled (ice-bath) and acidified with 2 M HCl (4 mL) anddiluted with H₂O (15 mL). The reaction mixture was then extracted intoEtOAc (2×50 mL) and the combined organic layer was dried (MgSO₄),filtered and evaporated to dryness to give the title compound as ayellow oil (213 mg, 80%).

Step 3: E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamideand E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide

To a solution of 1-phenyl-2,3-dihydro-1H-indene-1-carboxylic acid (210mg, 0.88 mmol) in DCM (7 mL) was added oxalyl chloride (149 μL, 1.76mmol). The reaction mixture was stirred at r.t for 20 h under anatmosphere of nitrogen. The reaction mixture was concentrated to drynessand redissolved in DCM (8 mL). To this was added aqueous hydroxylamine(1.5 mL, 50% solution) and the mixture stirred at r.t for 4 h. Themixture was cooled (ice-bath) and acidified with 2 M HCl (4 mL) anddiluted with H₂O (15 mL). The reaction mixture was then extracted intoEtOAc (2×50 mL) and the combined organics washed with brine (10 mL),dried (MgSO₄), filtered and concentrated. Purification by preparativeHPLC and chiral HPLC to give the E1-(abs) and E2-(abs) enantiomers (2 mgand 3 mg respectively) which were arbitrarily assigned. (Chiralpak IA20/80 IPA/MeOH (50/50/0.1% formic acid)/Heptane, 1.0 mL/min, RT 7.8 min(E1-(abs)) and 10.9 min (E2-(abs)). E1-(abs) LCMS (ES+) 254 (M+H)⁺, RT3.40 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆): 10.36 (1H, s),8.80 (1H, s), 7.55-7.51 (1H, m), 7.32-7.20 (6H, m), 7.11 (2H, d, J=7.3Hz), 3.00-2.86 (2H, m), 2.80-2.67 (1H, m), 2.20-2.11 (1H, m). E2-(abs)LCMS (ES+) 254 (M+H)⁺, RT 3.40 min (Analytical method 1); ¹H NMR δ(ppm)(DMSO-d₆): 10.38 (1H, s), 8.82 (1H, s), 7.54-7.51 (1H, m),7.32-7.20 (6H, m), 7.11 (2H, d, J=7.2 Hz), 2.99-2.86 (2H, m), 2.80-2.67(1H, m), 2.20-2.11 (1H, m).

Example 89: N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide

Step 1: 2-Phenyl-2,3-dihydro-1H-indene-2-carbonitrile

Benzyl cyanide (117 mg, 1.00 mmol), α,α′-dibromo-o-xylene (396 mg, 1.50mmol), NaOH (2 mL, 2 M aqueous solution, 4.00 mmol), benzyltriethylammonium bromide (408 mg, 1.50 mmol) and toluene (10 mL) werecombined and stirred at r.t. for 8 days. The reaction mixture was washedwith H₂O and the organics concentrated. Purification by flashchromatography (33% EtOAc in i-hex) gave the title compound as a clearoil (110 mg, 50%). LCMS (ES+) 220 (M+H)⁺.

Step 2: 2-Phenyl-2,3-dihydro-1H-indene-2-carboxylic acid

To a stirred solution of 2-phenyl-2,3-dihydro-1H-indene-2-carbonitrile(110 mg, 0.5 mmol) in EtOH/H₂O (5 mL, 3:2) was added NaOH (100 mg, 2.5mmol), and the mixture stirred at reflux for 2 days. The mixture wasdiluted with H₂O and washed with DCM. The aqueous portion was collected,acidified with 2 M HCl and extracted into EtOAc. The organics were dried(MgSO₄), filtered and concentrated to give the title compound as a whitesolid (97 mg, 82 mmol). LCMS (ES+) 239 (M+H)⁺.

Step 3: Ethyl 2-phenyl-2,3-dihydro-1H-indene-2-carboxylate

A solution of 2-phenyl-2,3-dihydro-1H-indene-2-carboxylic acid (97 mg,0.4 mmol) and conc. H₂SO₄ (1 drop) in EtOH (20 mL) was heated at refluxtemperature overnight. The reaction mixture was allowed to cool to r.t.,diluted with 2 M aqueous K₂CO₃ solution and extracted into DCM. Theorganics were passed through a phase separator and concentrated to givethe title compound as a white solid (95 mg, 88%). LCMS (ES+) 267 (M+H)⁺.

Step 4: N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide

Ethyl 2-phenyl-2,3-dihydro-1H-indene-2-carboxylate (96 mg, 0.37 mmol),aqueous hydroxylamine (2 mL, 50% solution) and sodium hydroxide (1 mL,15% solution) in MeOH (20 mL) were stirred at r.t. for 6 h. The reactionmixture was extracted with DCM, passed through a phase separator andconcentrated to give a white solid which was then triturated withpetroleum ether 60-80/Et₂O (1:1) to give the title compound as a whitesolid. LCMS (ES+) 254 (M+H)⁺. ¹H NMR δ (ppm)(DMSO-d₆): 10.67 (1H, s),8.69 (1H, s), 7.40 (2H, d, J=7.4 Hz), 7.36-7.29 (2H, m), 7.26-7.21 (3H,m), 7.14-7.10 (2H, m), 3.84 (2H, d, J=15.7 Hz), 3.18 (2H, d, J=15.7 Hz).

Example 90:(S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off-white solid (23 mg). LCMS (ES+) 404(M+H)⁺, RT 3.48 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.25-10.18 (1H, br s), 8.83-8.77 (1H, br s), 7.68 (1H, dd, J=2.8, 8.6Hz), 7.58 (1H, dd, J=5.6, 8.9 Hz), 7.47 (1H, s), 7.41-7.34 (1H, m),7.20-7.13 (1H, m), 7.11-7.04 (2H, m), 3.77 (1H, d, J=15.9 Hz), 3.45 (1H,d, J=14.8 Hz), 3.19-3.13 (1H, m), 2.88 (1H, d, J=16.1 Hz), 2.11 (3H, d,J=2.6 Hz).

Example 91:(S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

Prepared following the method described for Example 1. Preparative HPLCgave the title compound as an off-white solid (6 mg). LCMS (ES+) 382(M+H)⁺, RT 3.16 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.24 (1H, s), 8.85 (1H, s), 8.24 (1H, s), 7.14-7.03 (4H, m), 3.62 (1H,d, J=16.2 Hz), 3.49 (1H, d, J=16.7 Hz), 3.08 (2H, dd, J=6.4, 16.1 Hz),2.44 (6H, s), 2.17 (3H, d, J=2.6 Hz).

Examples 92, 93 and 94(S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide,(R)-1-benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamideand(R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

Step 1:(S)-Methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate and(R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate

Intermediate 3 (2.5 g, 1.0 mmol) was dissolved in dimethylformamidedimethylacetal (5.0 mL) and heated to 80° C. for 16 h. The cooledmixture was concentrated onto silica and purified by flash silica columnchromatography (gradient elution i-hex to 100% EtOAc in i-hex) to yieldthe title compounds as a pale yellow oil (1.8 g, 58%). LCMS (ES+) 306(M+H)⁺.

Step 2: (S)-Methyl5-(3-fluoro-2-methylphenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylateand (R)-methyl4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate

To a solution of(S)-methyl-3-((dimethylamino)methylene)-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate and(R)-methyl-2-(dimethylaminomethylene)-1-(3-fluoro-2-methyl-phenyl)-3-oxo-cyclopentanecarboxylate(2.75 g, 9.02 mmol) in acetic acid (9 mL) was added hydrazine (9 mL,9.00 mmol, 1 M in THF), and the mixture stirred at r.t for 15 min beforeheating to 55° C. for 3 h. The solvent was removed in vacuo and wateradded and then extracted with DCM. The organics were passed through aphase separator and concentrated. Purification by flash silicachromatography (elution with Et₂O) gave the title compounds (1.7 g,68%).

Step 3: (S)-Methyl1-benzyl-5-(3-fluoro-2-methylpIyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate,(R)-methyl1-benzyl-4-(3-fluoro-2-methylphenI-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylateand (R)-methyl2-benzyl-4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate

To a stirred suspension of (S)-methyl5-(3-fluoro-2-methylphenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylateand (R)-methyl4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate(0.77 g, 2.8 mmol) in DMF (5 mL) was added benzyl chloride (0.38 g, 3.0mmol) and cesium carbonate (1.0 g, 3.1 mmol) and the mixture stirred atr.t. for 3 days. The reaction was then diluted with water and extractedinto Et₂O. The combined organics were dried (MgSO₄), filtered andconcentrated. Purification by flash silica chromatography (elution withEt₂O) and preparative HPLC gave (S)-methyl1-benzyl-5-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate(143 mg, 14%) and (R)-methyl1-benzyl-4-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate(142 mg, 14%) and (R)-methyl2-benzyl-4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate(156 mg, 15%) as a separable mixture of isomers. LCMS (ES+) 365 (M+H)⁺.

Step 4:(S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide

To a stirred suspension of hydroxylamine hydrochloride (180 mg, 2.61mmol) in DCM (6 mL), under a nitrogen atmosphere, was added trimethylaluminium (1.2 mL, 2.4 mmol, 2 M THF solution). The mixture was stirredat r.t. for 20 min before a solution of (S)-methyl1-benzyl-5-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxylate(143 mg, 0.4 mmol) in DCM (4 mL) was added, and the mixture stirred foran additional 1.5 h. Additional hydroxylamine hydrochloride (180 mg,2.61 mmol) and trimethyl aluminium (1.2 mL, 2.4 mmol, 2 M THF solution)were added and stirring continued for 2 h. The reaction mixture wasquenched with 2 M HCl (3 mL), then the mixture concentrated to dryness,and partitioned between water and EtOAc. The organics were dried(MgSO₄), filtered and concentrated. Purification by preparative HPLCgave the title compound as a colorless solid (67 mg). LCMS (ES+) 366(M+H)⁺, RT 3.29 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.14 (1H, s), 8.76 (1H, s), 7.33-7.28 (3H, m), 7.15-7.11 (3H, m),7.08-7.02 (2H, m), 6.87 (1H, dd, J=2.1, 6.7 Hz), 5.27-5.20 (2H, m), 3.51(1H, d, J=16 Hz), 3.34 (1H, d, J=16 Hz), 2.98 (1H, d, J=16 Hz), 2.83(1H, d, J=16 Hz), 2.08 (3H, d, J=2.5 Hz).

Step 5:(R)-1-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

Following the same method as Step 4 starting from (R)-methyl1-benzyl-4-(3-fluoro-2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate(142 mg, 0.39 mmol). Purification by preparative HPLC gave the titlecompound as a colorless solid (99 mg). LCMS (ES+) 366 (M+H)⁺, RT 10.11min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.09 (1H, s), 8.69(1H, s), 7.46-7.45 (1H, m), 7.39-7.34 (2H, m), 7.33-7.27 (1H, m),7.26-7.22 (2H, m), 7.17-7.10 (1H, m), 7.09-7.02 (2H, m), 5.23 (2H, s),3.84-3.75 (1H, m), 2.78-2.68 (1H, m), 2.61-2.52 (1H, m), 2.30-2.20 (1H,m), 2.11 (3H, s).

Step 6:(R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

Following the same method as Step 4 starting from (R)-methyl2-benzyl-4-(3-fluoro-2-methylphenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxylate(156 mg, 0.43 mmol). Purification by preparative HPLC gave the titlecompound as a colorless solid (104 mg). LCMS (ES+) 366 (M+H)⁺, RT 9.94min (Analytical method 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.11 (1H, s), 8.70(1H, d, J=1.4 Hz), 7.68 (1H, s), 7.40-7.36 (2H, m), 7.33-7.28 (3H, m),7.16-7.03 (2H, m), 6.99 (1H, d, J=7.5 Hz), 5.33 (2H, s), 3.67-3.58 (1H,m), 2.79-2.70 (1H, m), 2.60-2.56 (1H, m), 2.21-2.15 (1H, m), 2.14 (3H,d, J=2.4 Hz).

Example 95:(R)-4-(3-fluoro-2-methylphenyl)-2-(2-fluorobenzyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

Prepared following the method described for Example 91, using 2-fluorobenzyl chloride (432 mg, 3.0 mmol) gave the title compound as acolorless solid (89 mg). LCMS (ES+) 384 (M+H)⁺, RT 10.01 min (Analyticalmethod 2); ¹H NMR δ (ppm)(DMSO-d₆): 10.11 (1H, s), 8.71 (1H, s), 7.69(1H, s), 7.43-7.36 (1H, m), 7.32-7.27 (1H, m), 7.25-7.20 (2H, m),7.16-7.04 (2H, m), 6.99 (1H, d, J=7.5 Hz), 5.39 (2H, s), 3.67-3.58 (1H,m), 2.77-2.69 (1H, m), 2.59-2.53 (1H, m), 2.20-2.15 (1H, m), 2.13 (3H,d, J=2.5 Hz).

Example 96:(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamideStep 1: Methyl5-(3-fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate

To a solution of methyl3-bromo-1-(3-fluoro-2-methylphenyl)-4-oxocyclopentanecarboxylate (500mg, 1.52 mmol) in ethanol (5 mL) was added5-fluoropyridine-2-carbothioamide (356 mg, 2.28 mmol). The reactionmixture heated to 110° C. under microwave conditions for 1 h. Thereaction mixture was concentrated to give a dark red gum. The crudereaction material was purified by flash silica chromatography (gradientelution i-hex to 40% EtOAc in i-hex) to give the title compound as abright orange solid (226 mg, 34%). Used crude (45% pure) without furtherpurification.

Step 2:5-(3-Fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide

To a solution of hydroxylamine hydrochloride (0.25 g, 3.68 mmol) in DCM(10 mL) was added trimethyl aluminum in heptane (1.6 mL, 3.3 mmol). Thena solution of methyl5-(3-fluoro-2-methylphenyl)-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxylate(226 mg, 0.58 mmol) in DCM (7 mL) was added dropwise and stirred for 1h. The reaction was treated with 2N HCl (6 mL) with cooling then MeOH(25 mL) was added and adjusted pH to 1 with 2N HCl. The solvent wasevaporated to leave the aqueous which was added to pH 5 with NaHCO₃ toprecipitate the aluminum which was filtered off through Celite washingwell with ethyl acetate. The phases were separated and the organicsevaporated to give a yellow solid which was purified by preparative HPLCto give the title compound as an off white solid (39 mg). LCMS (ES+) 388(M+H)⁺, RT 3.57 min (Analytical method 1); ¹H NMR δ (ppm)(DMSO-d₆):10.29 (1H, s), 8.84 (1H, s), 8.62 (1H, d, J=2.9 Hz), 8.09 (1H, dd,J=4.5, 8.9 Hz), 7.90-7.85 (1H, m), 7.19-7.06 (3H, m), 3.77 (2H, dd,J=15.6, 15.6 Hz), 3.42-3.36 (1H, m), 3.22 (1H, d, J=15.8 Hz), 2.17 (3H,d, J=2.6 Hz).

Table of Examples Example Structure IUPAC Name 1

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 2

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-l-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 3

(S)-5-(3-Fluoro-2-methylphenyl)-l-(2-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 4

(S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 5

(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 6

(S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 7

(S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 8

(S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 9

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 10

(S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 11

(S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 12

(S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 13

(S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 14

(S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 15

(S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 16

(S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2-yl)-N-hydroxy-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-5-carboxamide 17

(S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 18

(S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 19

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1- (pyrazin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 20

(S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 21

(S)-2-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 22

(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 23

(S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 24

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 25

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 26

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 27

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 28

(S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 29

(S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole- 5-carboxamide 30

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 31

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 32

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide 33

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide 34

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide 35

5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide and5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide 36

5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide and5-(3-fluoro-2-methylphenyl)-2-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide 37

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide 38

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5- carboxamide 39

3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide 40

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6- carboxamide 41

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2- (phenylsulfonamide)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide 42

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6- carboxamide 43

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6- carboxamide 44

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide 45

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide 46

2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide 47

6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxamide 48

(S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 6-carboxamide 49

(R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 5-carboxamide 50

(R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6- carboxamide 51

(S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5- carboxamide 52

(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6- carboxamide 53

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-isopropyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 54

(R)-4-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4- carboxamide 55

(S)-6-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6- carboxamide 56

(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-6-carboxamide57

(R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5- carboxamide 58

(S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 59

(R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4- carboxamide 60

(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-6-carboxamide 61

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 62

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 63

5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 64

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 65

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 66

(R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5- carboxamide 67

(S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5- carboxamide 68

(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 69

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 70

(R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 71

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H- cyclopenta[d]thiazole-5-carboxamide72

(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6- carboxamide 73

(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6- carboxamide 74

E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 75

E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 76

E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 77

E2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide 78

(S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6- carboxamide 79

(R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 80

E1-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5- carboxamide 81

E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5- carboxamide 82

2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide 83

2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d] pyrimidine-7-carboxamide 84

E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide 85

E2-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide 86

N-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6- carboxamide 87

E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene- 1-carboxamide 88

E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene- 1-carboxamide 89

N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2- carboxamide 96

(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-fluoropyridin-2-yl)-5,6-dihydroxy-4H-cyclopenta[d]thiazole-5-carboxamide 90

(S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 91

(S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide 92

(S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5- carboxamide 93

(R)-1-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4- carboxamide 94

(R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4- carboxamide 95

(R)-4-(3-fluoro-2-methylphenyl)-2-(2- flurobenzyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide

BIOLOGICAL EXAMPLES Example A: Analysis of Inhibition of HDAC4 with theCompounds

The potency of compounds is quantified by measuring the HistoneDeacetylase 4 (HDAC4) catalytic domain enzymatic activity using thefluorogenic substrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylatedto Boc-Lys-AMC by HDAC4. Cleavage by trypsin results in the release ofthe fluorophore AMC from the deacetylated substrate. The fluorescence ofthe sample is directly related to the histone deacetylase activity inthe sample.

Serially Dilute the Compounds.

Serial dilutions of the compounds being tested and control referencecompound(1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone)are made by first resuspending the lyophilized compound to a finalconcentration of 10 mM in 100% dimethyl sulfoxide (DMSO). Stocks of 60μL aliquots of the 10 mM compound in DMSO are prepared and stored at−20° C. From one stock aliquot of each compound to be tested and thereference compound, a 16-point serial dilution is prepared according toTable 1 using a 125 μL 16-channel Matrix multi-channel pipette (MatrixTechnologies Ltd).

TABLE 1 Serial Dilution of Compounds Concen- Diluted tration DilutionSolutions Well (μM) ratio Volumes Concentration 1 A 10000 — 60 μL 10 mMTest compound/ reference control Concentration 2 B 5000 1:2 30 μL A + 30μL DMSO Concentration 3 C 2500 1:2 30 μL B + 30 μL DMSO Concentration 4D 1000   1:2.5 30 μL C + 45 μL DMSO Concentration 5 E 500 1:2 30 μL D +30 μL DMSO Concentration 6 F 250 1:2 30 μL E + 30 μL DMSO Concentration7 G 125 1:2 30 μL F + 30 μL DMSO Concentration 8 H 62.5 1:2 30 μL G + 30μL DMSO Concentration 9 I 31.25 1:2 30 μL H + 30 μL DMSO Concentration10 J 15.63 1:2 30 μL I + 30 μL DMSO Concentration 11 K 7.81 1:2 30 μLJ + 30 μL DMSO Concentration 12 L 3.91 1:2 30 μL K + 30 μL DMSOConcentration 13 M 1.95 1:2 30 μL L + 30 μL DMSO Concentration 14 N 0.981:2 30 μL M + 30 μL DMSO Concentration 15 O 0.49 1:2 30 μL N + 30 μLDMSO Concentration 16 P 0.24 1:2 30 μL O + 30 μL DMSO

2 μL (200×) of each diluted solution and each control (full activity:100% DMSO alone or full inhibition 1 mM) is stamped into V-bottomedpolypropylene 384-well compound plates using either the Bravo (384-wellhead from Agilent) or 12.5 μL 16-channel Matrix multi-channel pipette(Matrix Technologies Ltd). Each well with the 200× compound solution isdiluted 1:20 by the addition of 38 μL assay buffer+DMSO (10.5% DMSO, 45mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and 0.9 mM MgCl₂ at pH 8.0 andequilibrated to room temperature).

Prepare HDAC4 Catalytic Domain Enzyme (0.2 μg/mL).

The HDAC4 catalytic domain enzyme is human catalytic domain HDAC4protein (amino acids 648-1032) with a C-terminal 6× histidine tag,produced by BioFocus. A working solution of enzyme is prepared from a500 μg/mL stock aliquot of HDAC4 catalytic domain (thawed on ice)diluted to 0.2 μg/mL with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7mM KCl, and 1 mM MgCl₂ at pH 8 and equilibrated to room temperature)just prior to the addition of the enzyme to the assay.

Prepare 5× (50 μM) Boc-Lys(Tfa)-AMC Substrate.

5× (50 μM) substrate is prepared just prior to the addition to theassay. A 1 mM substrate stock is made by diluting a 100 mMBoc-Lys(Tfa)-AMC in DMSO solution 1:100 by adding it drop-wise to assaybuffer (equilibrated to room temperature) while vortexing at slow speedto prevent precipitation. The 5× substrate is prepared by diluting the 1mM substrate solution 1:20 by adding it drop-wise to assay buffer(equilibrated to room temperature) while vortexing at slow speed toprevent precipitation.

Prepare 3× (30 μM) Developer/Stop Solution.

3× (30 μM) Developer/Stop Solution is prepared just prior to addition tothe plate by diluting a stock solution of 10 mM reference compound 1:333in 25 mg/mL trypsin (PAA Laboratories Ltd.) equilibrated to roomtemperature.

Assay.

5 μL of each solution of 1:20 diluted compound from above is transferredto a clear bottomed, black, 384-well assay plate using the Bravo or theJanus (384-well MDT head from Perkin Elmer). Using a 16-channel Matrixmulti-channel pipette, 35 μL of the working solution of HDAC4 catalyticdomain enzyme (0.2 μg/mL in assay buffer) is transferred to the assayplate. The assay is then started by adding 10 μL of 5× (50 μM) substrateto the assay plates using either the Bravo, Janus or 16-channel Matrixmulti-channel pipette. The assay plate is then shaken for two minutes onan orbital shaker at 900 rpm (rotations per minute). Next the plate isincubated for 15 minutes at 37° C. The reaction is stopped by adding 25μL of 3× (30 μM) developer/stop solution to the assay plates usingeither the Bravo, Janus or a 16-channel Matrix multi-channel pipette.Assay plates are then shaken for 5 minutes on an orbital shaker at 1200rpm. Next, the assay plates are incubated at 37° C. for 1 hour in atissue culture incubator. Finally, the fluorescence is measured(Excitation: 355 nm, Emission: 460 nm) using PerkinElmer EnVision in topread mode.

Example B: Analysis of Inhibition of HDAC5 with the Compounds

The potency of the compounds is quantified by measuring the HistoneDeacetylase 5 (HDAC5) enzymatic activity using the fluorogenicsubstrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylated toBoc-Lys-AMC by HDAC5. Cleavage by trypsin results in the release of thefluorophore AMC from the deacetylated substrate. The fluorescence of thesample is directly related to the histone deacetylase activity in thesample.

Serially Dilute the Compounds.

Serial dilutions of the compounds and control reference compound(1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone)are made by first resuspending the lyophilized compound to a finalconcentration of 10 mM in 100% DMSO. Stocks of 60 μL aliquots of the 10mM compound in DMSO are prepared and stored at −20° C. From one stockaliquot of each compound to be tested and the reference compound, a16-point serial dilution is prepared according to Table 1 using a 125 μL16-channel Matrix multi-channel pipette.

2 μL (200×) of each diluted solution and each control (full activity:100% DMSO alone or full inhibition 1 mM) is stamped into V-bottompolypropylene 384-well compound plates using either Bravo, Janus, or a12.5 μL 16-channel Matrix multi-channel pipette. Each well with the 2 μLof the 200× stamped compound solution is diluted 1:20 by the addition of38 μl assay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mMKCl, and 0.9 mM MgCl₂ at pH 8.0 and equilibrated to 37° C.).

Prepare HDAC5 Catalytic Domain Enzyme (0.57 μg/mL).

The HDAC5 catalytic domain enzyme is human HDAC5 catalytic domain(GenBank Accession No. NM_001015053), amino acids 657-1123 with aC-terminal His tag and can be obtained from BPS BioScience. The proteinis 51 kDa and is expressed in a baculovirus expression system. A workingsolution of enzyme is prepared from a 1.65 mg/mL stock aliquot of HDAC5catalytic domain (thawed on ice) diluted to 0.57 μg/mL with assay buffer(50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl₂ at pH 8 andequilibrated to 37° C.) just prior to the addition of the enzyme to theassay.

Prepare 5× (40 μM) Boc-Lys(Tfa)-AMC Substrate.

5× (40 μM) substrate is prepared just prior to the addition to theassay. The 5× substrate is prepared by diluting the 100 mMBoc-Lys(Tfa)-AMC in DMSO solution 1:2500 by adding it drop-wise to assaybuffer (equilibrated to 37° C.) while vortexing at slow speed to preventprecipitation.

Prepare 3× (30 μM) Developer/Stop Solution.

3× (30 μM) Developer/Stop Solution is prepared just prior to addition tothe plate by diluting a stock solution of 10 mM reference compound 1:333in 25 mg/mL trypsin equilibrated to 37° C.

Assay.

5 μL of each solution of the 1:20 diluted compounds and controls fromabove is transferred to a clear bottomed, black, 384-well assay plateusing the Bravo or Janus. Using a 16-channel Matrix multi-channelpipette, 35 μL of the working solution of the HDAC5 catalytic domainenzyme (0.57 μg/mL in assay buffer) is transferred to the assay plate.The assay is then started by adding 10 μL of 5× (40 μM) substrate to theassay plates using either the Bravo, Janus or 16-channel Matrixmulti-channel pipette. The assay plate is then shaken for one minute onan orbital shaker at 900 rpm. Next, the plates are incubated for 15minutes at 37° C. The reaction is stopped by adding 25 μL of 3× (30 μM)developer/stop solution to the assay plates using either the Bravo,Janus or a 16-channel Matrix multi-channel pipette. Assay plates arethen shaken for 2 minutes on an orbital shaker at 900 rpm. Next, theassay plates are incubated at 37° C. for 1 hour in a tissue cultureincubator followed by shaking for 1 minute at the maximum rpm on anorbital shaker before reading on the EnVision. Finally, the fluorescenceis measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmerEnVision in top read mode.

Example C: Analysis of Inhibition of HDAC7 with the Compounds

The potency of the compounds is quantified by measuring the HistoneDeacetylase 7 (HDAC7) enzymatic activity using the fluorogenicsubstrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylated toBoc-Lys-AMC by HDAC7. Cleavage by trypsin results in the release of thefluorophore AMC from the deacetylated substrate. The fluorescence of thesample is directly related to the histone deacetylase activity in thesample.

Serially Dilute HDAC Inhibitor Compounds.

Serial dilutions of the compounds to be tested and control referencecompound(1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone)are made by first resuspending the lyophilized compound to a finalconcentration of 10 mM in 100% DMSO. Stocks of 60 μL, aliquots of the 10mM compound in DMSO are prepared and stored at −20° C. From one stockaliquot of each compound to be tested and the reference compound, a16-point serial dilution is prepared according to Table 1 using a 125μL, 16-channel Matrix multi-channel pipette.

2 μL (200×) of each diluted solution and each control (full activity:100% DMSO alone or full inhibition 1 mM) is stamped into V-bottompolypropylene 384-well compound plates using either the Bravo, Janus, ora 12.5 μL, 16-channel Matrix multi-channel pipette. Each well with the200× compound solution is diluted 1:20 by the addition of 38 μL assaybuffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl, and0.9 mM MgCl₂ at pH 8.0 and equilibrated to 37° C.).

Prepare HDAC7 Enzyme (71 ng/mL).

The HDAC7 enzyme is human HDAC7 (GenBank Accession No. AY302468) aminoacids 518-end with a N-terminal Glutathione S-transferase (GST) tag andcan be obtained from BPS BioScience. The protein is 78 kDa and isexpressed in a baculovirus expression system. A working solution ofenzyme is prepared from a 0.5 mg/ml stock aliquot of HDAC7 (thawed onice) diluted to 71 ng/mL with assay buffer (50 mM Tris-HCl, 137 mM NaCl,2.7 mM KCl, and 1 mM MgCl₂ at pH 8 and equilibrated to 37° C.) justprior to the addition of enzyme to the assay.

Prepare 5× (50 μM) Boc-Lys(Tfa)-AMC Substrate.

5× (50 μM) substrate is prepared just prior to the addition to theassay. The 5× substrate is prepared by diluting a 100 mMBoc-Lys(Tfa)-AMC in DMSO solution 1:2000 by adding it drop-wise to assaybuffer (equilibrated to 37° C.) while vortexing at slow speed to preventprecipitation.

Prepare 3× (30 μM) Developer/Stop Solution.

3× (30 μM) Developer/Stop Solution is prepared just prior to addition tothe plate by diluting a stock solution of 10 mM reference compound 1:333in 25 mg/mL trypsin equilibrated to 37° C.

Assay.

5 μL of each solution of 1:20 diluted compound from above is transferredto a clear bottomed, black, 384-well assay plate using the Bravo orJanus. Using a 16-channel Matrix multi-channel pipette, 35 μL of theworking solution of the HDAC7 enzyme (71 ng/mL in assay buffer) istransferred to the assay plate. The assay is then started by adding 10μL of 5× (50 μM) substrate to the assay plate using either the Bravo,Janus or 16-channel Matrix multi-channel pipette. The assay plate isthen shaken for one minute on an orbital shaker at 900 rpm. Next, theplate is incubated for 15 minutes at 37° C. The reaction is then stoppedby adding 25 μL of 3× (30 μM) developer/stop solution to the assayplates using either the Bravo, Janus or a 16-channel Matrixmulti-channel pipette. The assay plate is then shaken for 2 minutes onan orbital shaker at 900 rpm. Next, the assay plate is incubated at 37°C. for 1 hour in a tissue culture incubator followed by shaking for 1minute at maximum rpm on an orbital shaker. Finally, the fluorescence ismeasured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmerEnVision in top read mode.

Example D: Analysis of Inhibition of HDAC9 with the Compounds

The potency of the compounds is quantified by measuring the HistoneDeacetylase 9 (HDAC9) enzymatic activity using the fluorogenicsubstrate, Boc-Lys(Tfa)-AMC. The substrate is deacetylated toBoc-Lys-AMC by HDAC9. Cleavage by trypsin results in the release of thefluorophore AMC from the deacetylated substrate. The fluorescence of thesample is directly related to the histone deacetylase activity in thesample.

Serially Dilute the Compounds.

Serial dilutions of the compounds and control reference compound(1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone)are made by first resuspending the lyophilized compound to a finalconcentration of 10 mM in 100% DMSO. Stocks of 60 μL aliquots of the 10mM compound in DMSO are prepared and stored at −20° C. From one stockaliquot of each compound to be tested and the reference compound, a16-point serial dilution is prepared according to Table 1 using a 125 μL16-channel Matrix multi-channel pipette.

2 μL (200×) of each diluted solution and each control (full activity:100% DMSO alone or full inhibition 1 mM) is stamped into V-bottompolypropylene 384-well compound plates using either the Bravo, Janus, or12.5 μL 16-channel Matrix multi-channel pipette. Each well with thestamped 200× compound solution is diluted 1:20 by the addition of 38 μLassay buffer+DMSO (10.5% DMSO, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl,and 0.9 mM MgCl₂ at pH 8.0 and equilibrated to 37° C.).

Prepare HDAC9 Enzyme (0.57 μg/mL).

The HDAC9 enzyme is human HDAC9 (GenBank Accession No. NM_178423) aminoacids 604-1066 with a C-terminal His tag and can be obtained from BPSBioScience. The protein is 50.7 kDa and is expressed in a baculovirusexpression system. A working solution of enzyme is prepared from a 0.5mg/mL stock aliquot of HDAC9 (thawed on ice) diluted to 0.57 μg/mL withassay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl₂ atpH 8 and equilibrated to 37° C.) just prior to the addition of enzyme tothe assay.

Prepare 5× (125 μM) Boc-Lys(Tfa)-AMC Substrate.

5× (125 μM) substrate is prepared just prior to the addition to theassay. The 5× substrate is prepared by diluting a 100 mMBoc-Lys(Tfa)-AMC in DMSO solution 1:800 by adding it drop-wise to assaybuffer (equilibrated to 37° C.) while vortexing at slow speed to preventprecipitation.

Prepare 3× (30 μM) Developer/Stop Solution.

3× (30 μM) Developer/Stop Solution is prepared just prior to addition tothe plate by diluting a stock solution of 10 mM reference compound 1:333in 25 mg/mL trypsin equilibrated to 37° C.

Assay.

5 μL of each solution of 1:20 diluted compound from above is transferredto a clear bottomed, black, 384-well assay plate using the Bravo orJanus. Using a 16-channel Matrix multi-channel pipette, 35 μL of theworking solution of the HDAC9 enzyme (0.57 μg/mL in assay buffer) istransferred to the assay plate. The assay is then started by adding 10μL of 5× (125 μM) substrate to the assay plate using either the Bravo,Janus or 16-channel Matrix multi-channel pipette. The assay plate isthen shaken for one minute on an orbital shaker at 900 rpm. Next, theplate is incubated for 15 minutes at 37° C. The reaction is stopped byadding 25 μL of 3× developer/stop solution to the assay plates usingeither the Bravo, Janus or a 16-channel Matrix multi-channel pipette.The assay plate is then shaken for 2 minutes on an orbital shaker at 900rpm. Next, the assay plate is incubated at 37° C. for 1 hour in a tissueculture incubator followed by shaking for 1 minute at maximum rpm on anorbital shaker before reading on the enVision. Finally, the fluorescenceis measured (Excitation: 355 nm, Emission: 460 nm) using PerkinElmerEnVision in top read mode.

Example E: Analysis of Inhibition of Cellular HDAC Activity with theCompounds

The potency of the compounds is quantified by measuring the cellularhistone deacetylase enzymatic activity using the fluorogenic substrate,Boc-Lys(Tfa)-AMC. After penetration in Jurkat E6-1 cells, the substrateis deacetylated to Boc-Lys-AMC. After cell lysis and cleavage bytrypsin, the fluorophore AMC is released from the deacetylated substrateonly. The fluorescence of the sample is directly related to the histonedeacetylase activity in the sample.

Jurkat E6.1 Cell Culture and Plating.

Jurkat E6.1 cells are cultured according to standard cell cultureprotocols in Jurkat E6.1 Growth Media (RPMI without phenol red, 10% FBS,10 mM HEPES, and 1 mM Sodium Pyruvate). Jurkat E6.1 cells are countedusing a Coulter Counter and resuspended in Jurkat E6.1 growth media at aconcentration of 75,000 cells/35 μL. 35 μL or 75,000 cells is seededinto Greiner microtitre assay plates. The plates are then incubated at37° C. and 5% CO₂ while other assay components are being prepared.

Serially Dilute the Compounds.

Serial dilutions of the compounds being tested and control referencecompound(1-(5-(3-((4-(1,3,4-oxadiazol-2-yl)phenoxy)methyl)-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2,2,2-trifluoroethanone)are made by first resuspending the lyophilized compound to a finalconcentration of 10 mM in 100% DMSO. Stocks of 70 μL aliquots of the 10mM compound in DMSO are prepared and stored at −20° C. From one stockaliquot of each compound to be tested and the reference compound, a16-point serial dilution is prepared according to Table 1 using a 125 μL16-channel Matrix multi-channel pipette.

2 μL (200×) of each diluted solution and each control (full activity:100% DMSO alone or full inhibition 1 mM) is stamped into V-bottompolypropylene 384-well compound plates using either the Bravo, Janus, or12.5 μL 16-channel Matrix multi-channel pipette. Each well with the 200×compound solution is diluted 1:20 by the addition of 38 μL Jurkat assaybuffer+DMSO (9.5% DMSO, RPMI without phenol red, 0.09% FBS, 9 mM Hepes,and 0.9 mM Sodium Pyruvate equilibrated to room temperature)

Prepare 5× (500 μM) Boc-Lys(Tfa)-AMC Substrate.

5× (500 μM) substrate is prepared just prior to the addition to theassay. The 5× substrate is prepared by diluting a 100 mMBoc-Lys(Tfa)-AMC in DMSO solution 1:200 by adding it drop-wise to Jurkatassay medium (RPMI without phenol red, 0.1% FBS, 10 mM Hepes, and 1 mMSodium Pyruvate equilibrated to 37° C.) while vortexing at slow speed toprevent precipitation.

Prepare 3× Lysis Buffer.

10 mL of 3× lysis buffer is prepared with 8.8 ml of 3× stock lysisbuffer (50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂, 1%Nonidet P40 Substitute equilibrated to room temperature) and 1.2 mL of 3mg/mL Trypsin equilibrated to room temperature.

Assay.

5 μL of each solution of 1:20 diluted compound from above is transferredto the Greiner microtitre assay plates with 75,000 cells/well using theBravo. Cells are then incubated for 2 hours at 37° C. and 5% CO₂. Theassay is then started by adding 10 μL of 5× (500 μM) substrate to theassay plate using either the Bravo or 16-channel Matrix multi-channelpipette. The cells are then incubated for 3 hours at 37° C. and 5% CO₂.Next, 25 μL of 3× lysis buffer is added to each well using either the125 μL 16 channel pipette or the Bravo. The assay plate is thenincubated overnight (15-16 hours) at 37° C. and 5% CO₂. The followingday, the plates are shaken on an orbital shaker for 1 minute at 900 rpm.Finally the top read fluorescence (Excitation: 355 nm, Emission: 460 nm)is measured using PerkinElmer EnVision.

Example F

Using the assay protocols described above, the following compoundssynthesized by the above synthetic methods were tested.

Cell (Lys- Cell (Lys-Ac) Biochemical TFA) IC₅₀ IC₅₀ Example StructureIC₅₀ (μM) (μM) (μM) 1

0.028 0.059 >50 2

0.023 0.014 >50 3

0.017 0.033 >50 4

0.061 0.072 >50 5

0.053 0.099 >50 6

0.044 0.067 >50 7

0.015 0.013 >50 8

0.112 0.103 >50 9

0.039 0.082 >50 10

0.017 0.017 >50 11

0.012 0.027 >50 12

0.021 0.018 >50 13

0.027 0.012 >50 14

0.015 0.011 >50 15

0.019 0.032 >50 16

0.031 0.069 >50 17

0.029 0.039 >50 18

0.037 0.163 >50 19

0.038 0.053 >50 20

0.109 0.25 >50 21

0.147 0.175 >50 22

0.044 0.011 >50 23

0.197 0.134 >50 24

0.028 0.064 >50 25

0.076 0.160 >50 26

0.057 0.071 >50 27

0.053 0.116 >50 28

0.065 0.069 >50 29

0.104 0.069 >50 30

1.0 1.7 >50 31

0.82 0.072 >50 32

17.3 2.9 >50 33

0.71 0.41 >50 34

19.8 26.7 >50 35

1.7 0.77 >50 36

0.60 0.37 >50 37

1.1 0.086 >50 38

7.9 11.2 >50 39

4.4 1.8 >50 40

1.6 0.58 >50 41

0.19 1.6 >50 42

0.77 0.32 >50 43

1.9 0.66 >50 44

1.0 1.5 >50 45

3.7 2.6 >50 46

1.6 0.76 >50 47

3.2 1.1 >50 48

0.156 0.060 >50 49

0.102 0.25 >50 50

0.22 0.12 >50 51

0.27 1.4 >50 52

0.16 0.21 >50 53

0.067 0.23 >50 54

0.072 0.32 >50 55

0.29 0.26 >50 56

0.88 1.8 >50 57

19.4 >50 >50 58

0.048 0.125 >50 59

0.100 0.72 >50 60

0.22 0.20 >50 61

0.48 0.12 >50 62

0.193 0.049 >50 63

0.49 0.038 >50 64

0.21 0.11 >50 65

0.53 0.22 >50 66

0.081 0.098 >50 67

0.193 0.29 >50 68

0.24 0.12 >50 69

0.044 0.035 >50 70

0.122 0.079 >50 71

0.095 0.056 >50 72

0.094 0.79 >50 73

0.143 0.63 >50 74

0.78 0.54 >50 75

0.27 0.051 >50 76

0.068 0.036 >50 77

0.20 0.128 >50 78

0.12 0.50 >50 79

0.053 0.026 36.5 80

0.079 0.045 >50 81

9.7 5.6 >50 82

0.11 1.8 >50 83

1.3 0.49 >50 84

0.48 1.4 >50 85

0.79 1.8 >50 86

8.2 46.7 >50 87

5.67 45.7 >50 88

>50 >50 >50 89

15.3 >50 >50 96

0.051 0.060 >50 90

0.036 0.015 >50 91

0.28 0.46 >50 92

0.048 0.027 >50 93

0.027 0.17 >50 94

0.82 2.78 >50 95

0.71 2.98 >50

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is—C(O)NH(OH) or —N(OH)C(O)R⁹; R² is aryl, heteroaryl, orheterocycloalkyl, each of which is optionally substituted with 1 to 3substituents independently chosen from halo, alkyl, cycloalkyl,haloalkyl, hydroxyl, alkoxy, and nitrile; A is aryl or heteroaryl; R³and R⁴ are independently chosen from hydrogen, alkyl, halo, —NHSO₂R¹⁰,C(O)NR¹¹R¹², NR¹¹R¹², nitrile, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, and heteroaralkyl, each of which is optionallysubstituted with 1 to 3 substituents independently chosen from halo,alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl,heteroaryl, and nitrile, wherein alkyl and alkoxy are optionallysubstituted with amino, (alkyl)amino or di(alkyl)amino; for eachoccurrence, R⁵, R⁶, R⁷, and R⁸ are independently chosen from hydrogenand lower alkyl; R⁹ is hydrogen or lower alkyl; R¹⁰ is lower alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R¹¹ and R¹² areindependently chosen from hydrogen, lower alkyl, alkoxy, lower haloalkyland cycloalkyl, wherein alkyl and alkoxy are optionally substituted withamino, (alkyl)amino or di(alkyl)amino, and m and m′ are independentlychosen from 0, 1, 2, 3 and 4, provided that 2≤(m+m′)≤4.
 2. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound of Formula I is a compound of Formula II:


3. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein R³ is phenyl optionally substituted with one or twosubstituents independently chosen from alkyl, haloalkyl, alkoxy,haloalkoxy, and halo.
 4. The compound of claim 3, or a pharmaceuticallyacceptable salt thereof, wherein R³ is phenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-chloro-2-fluorophenyl, 2,6-difluorophenyl, 2,5-dimethylphenyl,2,6-dimethylphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-methylphenyl,2,4-difluorophenyl, 4-(difluoromethoxy)phenyl, or3-fluoro-2-methylphenyl.
 5. The compound of claim 2, or apharmaceutically acceptable salt thereof, wherein R³ is pyridin-2-yl,pyridin-4-yl, or pyrazin-2-yl, each of which is optionally substitutedwith one or two substituents independently chosen from alkyl and halo.6. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein R³ is 5-fluoropyridin-2-yl, pyrazin-2-yl, or3-methylpyridin-4-yl.
 7. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein R³ is cyclopropyl or cyclopentyl, eachof which is optionally substituted with one or two substituentsindependently chosen from alkyl and halo.
 8. The compound of claim 7, ora pharmaceutically acceptable salt thereof, wherein R³ is cyclopropyl orcyclopentyl.
 9. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein R³ is isopropyl.
 10. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein R⁴ ishydrogen.
 11. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound of Formula I is a compound of FormulaIII:


12. The compound of claim 11, or a pharmaceutically acceptable saltthereof, wherein R³ is alkyl, haloalkyl, or aralkyl optionallysubstituted with halo.
 13. The compound of claim 12, or apharmaceutically acceptable salt thereof, wherein R³ is methyl,2,2,2,-trifluoroethyl, or 4-fluorobenzyl.
 14. The compound of claim 11,or a pharmaceutically acceptable salt thereof, wherein R³ is phenyloptionally substituted with one or two substituents independently chosenfrom alkyl, haloalkyl, alkoxy, haloalkoxy, and halo.
 15. The compound ofclaim 14 or a pharmaceutically acceptable salt thereof, wherein R³ is2-fluorophenyl, 4-(difluoromethoxy)phenyl, 4-fluoro-2-methylphenyl, or3-methylphenyl.
 16. The compound of claim 11, or a pharmaceuticallyacceptable salt thereof, wherein R³ is pyridin-2-yl or pyridin-4-yl,each of which is optionally substituted with one or two substituentsindependently chosen from alkyl and halo.
 17. The compound of claim 16,or a pharmaceutically acceptable salt thereof, wherein R³ is3-methylpyridin-4-yl, 3-chloropyridin-2-yl, or 3-fluoropyridin-2-yl. 18.The compound of claim 11, or a pharmaceutically acceptable salt thereof,wherein R⁴ is hydrogen, cyclopropyl, or phenyl optionally substitutedwith halo.
 19. The compound of claim 18, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is hydrogen.
 20. A compound ofFormula I is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is—C(O)NH(OH) or —N(OH)C(O)R⁹; R² is aryl, heteroaryl, orheterocycloalkyl, each of which is optionally substituted with 1 to 3substituents independently chosen from halo, alkyl, cycloalkyl,haloalkyl, hydroxyl, alkoxy, and nitrile; R³ and R⁴ are independentlychosen from hydrogen, alkyl, halo, —NHSO₂R¹⁰, C(O)NR¹¹R¹², NR¹¹R¹²,nitrile, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, andheteroaralkyl, each of which is optionally substituted with 1 to 3substituents independently chosen from halo, alkyl, cycloalkyl,haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl, heteroaryl, and nitrile,wherein alkyl and alkoxy are optionally substituted with amino,(alkyl)amino or di(alkyl)amino; for each occurrence, R⁵, R⁶, R⁷, and R⁸are independently chosen from hydrogen and lower alkyl; R⁹ is hydrogenor lower alkyl; R¹⁰ is lower alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; R¹¹ and R¹² are independently chosen from hydrogen, loweralkyl, alkoxy, lower haloalkyl and cycloalkyl, wherein alkyl and alkoxyare optionally substituted with amino, (alkyl)amino or di(alkyl)amino,and m and m′ are independently chosen from 0, 1, 2, 3 and 4, providedthat 2≤(m+m′)≤4.
 21. The compound of claim 20, or a pharmaceuticallyacceptable salt thereof, wherein R³ is hydrogen.
 22. The compound ofclaim 20, or a pharmaceutically acceptable salt thereof, wherein R⁴ iscyclopropyl.
 23. A compound of Formula I is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is—C(O)NH(OH) or —N(OH)C(O)R⁹; R² is aryl, heteroaryl, orheterocycloalkyl, each of which is optionally substituted with 1 to 3substituents independently chosen from halo, alkyl, cycloalkyl,haloalkyl, hydroxyl, alkoxy, and nitrile; R³ is hydrogen, alkyl, halo,—NHSO₂R¹⁰, C(O)NR¹¹R¹², NR¹¹R¹², nitrile, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionallysubstituted with 1 to 3 substituents independently chosen from halo,alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl,heteroaryl, and nitrile, wherein alkyl and alkoxy are optionallysubstituted with amino, (alkyl)amino or di(alkyl)amino; for eachoccurrence, R⁵, R⁶, R⁷, and R⁸ are independently chosen from hydrogenand lower alkyl; R⁹ is hydrogen or lower alkyl; R¹⁰ is lower alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R¹¹ and R¹² areindependently chosen from hydrogen, lower alkyl, alkoxy, lower haloalkyland cycloalkyl, wherein alkyl and alkoxy are optionally substituted withamino, (alkyl)amino or di(alkyl)amino, and m and m′ are independentlychosen from 0, 1, 2, 3 and 4, provided that 2≤(m+m′)≤4.
 24. The compoundof claim 23, or a pharmaceutically acceptable salt thereof, wherein R³is: hydrogen, cycloalkyl optionally substituted with one or two groupsindependently chosen from halo, alkyl, haloalkyl, and alkoxy, heteroaryloptionally substituted with one or two groups independently chosen fromhalo, alkyl, haloalkyl, and alkoxy, phenyl optionally substituted withone or two groups independently chosen from halo, alkyl, haloalkyl, andalkoxy, benzyl optionally substituted on the aromatic portion with oneor two groups independently chosen from halo, alkyl, haloalkyl, andalkoxy, or —NHS(O)₂R¹⁰, where R¹⁰ is phenyl.
 25. The compound of claim24, or a pharmaceutically acceptable salt thereof, wherein R³ ishydrogen, cyclopropyl, phenyl optionally substituted with one or twogroups independently chosen from fluoro and methyl, pyrimidin-5-yl,1H-pyrazol-5-yl optionally substituted with methyl, 1H-pyrazol-4-yloptionally substituted with methyl, pyridin-2-yl optionally substitutedwith methoxy, benzyl optionally substituted on the aromatic portion withtrifluoromethyl, or —NHS(O)₂R¹⁰, where R¹⁰ is phenyl.
 26. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound of Formula I is a compound of Formula VI:


27. The compound of claim 26, or a pharmaceutically acceptable saltthereof, wherein R³ is hydrogen, alkyl, haloalkyl, cycloalkyl, phenyloptionally substituted with halo, or heteroaryl.
 28. The compound ofclaim 27, or a pharmaceutically acceptable salt thereof, wherein R³ ishydrogen, trifluoromethyl, cyclopropyl, phenyl optionally substitutedwith halo, or pyridin-3-yl.
 29. The compound of claim 26, or apharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen. 30.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound of Formula I is a compound of Formula VII:


31. The compound of claim 30, or a pharmaceutically acceptable saltthereof, wherein R³ is hydrogen.
 32. The compound of claim 30, or apharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.
 33. Acompound of Formula I is a compound of Formula VIII:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is—C(O)NH(OH) or —N(OH)C(O)R⁹; R² is aryl, heteroaryl, orheterocycloalkyl, each of which is optionally substituted with 1 to 3substituents independently chosen from halo, alkyl, cycloalkyl,haloalkyl, hydroxyl, alkoxy, and nitrile; R³ is hydrogen, alkyl, halo,—NHSO₂R¹⁰, C(O)NR¹¹R¹², NR¹¹R¹², nitrile, cycloalkyl, heterocycloalkyl,aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionallysubstituted with 1 to 3 substituents independently chosen from halo,alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, aryl,heteroaryl, and nitrile, wherein alkyl and alkoxy are optionallysubstituted with amino, (alkyl)amino or di(alkyl)amino; for eachoccurrence, R⁵, R⁶, R⁷, and R⁸ are independently chosen from hydrogenand lower alkyl; R⁹ is hydrogen or lower alkyl; R¹⁰ is lower alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R¹¹ and R¹² areindependently chosen from hydrogen, lower alkyl, alkoxy, lower haloalkyland cycloalkyl, wherein alkyl and alkoxy are optionally substituted withamino, (alkyl)amino or di(alkyl)amino, and m and m′ are independentlychosen from 0, 1, 2, 3 and 4, provided that 2 ≤(m+m′)≤4.
 34. Thecompound of claim 33, or a pharmaceutically acceptable salt thereof,wherein R³ is phenyl optionally substituted with 1 to 3 substituentsindependently chosen from halo, alkyl, cycloalkyl, haloalkyl, hydroxyl,and alkoxy.
 35. The compound of claim 34, or a pharmaceuticallyacceptable salt thereof, wherein R³ is phenyl.
 36. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R² is aryloptionally substituted with 1 to 3 substituents independently chosenfrom halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, alkoxy, and nitrile.37. The compound of claim 36, or a pharmaceutically acceptable saltthereof, wherein R² is phenyl optionally substituted with 1 to 3substituents independently chosen from halo, alkyl, cycloalkyl,haloalkyl, hydroxyl, alkoxy, and nitrile.
 38. The compound of claim 37,or a pharmaceutically acceptable salt thereof, wherein R² is phenyloptionally substituted with 1 to 3 substituents independently chosenfrom halo and alkyl.
 39. The compound of claim 38, or a pharmaceuticallyacceptable salt thereof, wherein R² is phenyl and3-fluoro-2-methylphenyl.
 40. The compound of claim 39, or apharmaceutically acceptable salt thereof, wherein R² is3-fluoro-2-methylphenyl.
 41. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein m is 1 and m′ is 1.42. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein m is 1 and m′ is
 2. 43. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein m is 0 and m′ is 2.44. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein m is 2 and m′ is
 2. 45. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is —N(OH)C(O)R⁹.46. The compound of claim 45, or a pharmaceutically acceptable saltthereof, wherein R⁹ is lower alkyl.
 47. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is —C(O)NH(OH). 48.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein, for each occurrence, R⁵, R⁶, R⁷, and R⁸ are hydrogen.
 49. Acompound, or a pharmaceutically acceptable salt thereof, selected from:(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(3-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-1-(3-fluorophenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(4-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(p-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(3-Chloro-2-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(2,6-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(2,5-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(2,6-Dimethylphenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(2-Chloro-6-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-1-(2-fluoro-6-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-1-(5-fluoropyridin-2-yl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(2,4-Difluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-Cyclopentyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(pyrazin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-2-(4-(Difluoromethoxy)phenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-1-(4-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(m-tolyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(m-tolyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(3-methylpyridin-4-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-methylpyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-2-(3-Chloropyridin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;and5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;5-(3-Fluoro-2-methylphenyl)-1-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-1H-indazole-5-carboxamideand5-(3-fluoro-2-methylphenyl)-2-(4-fluorobenzyl)-N-hydroxy-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;E1-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;E2-(abs)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;3-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4-oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carboxamide;6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(phenylsulfonamido)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;6-(3-Fluoro-2-methylphenyl)-N-hydroxy-4,5,6,7-tetrahydrobenzo[d]thiazole-6-carboxamide;6-(3-Fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide;2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6,7,8-tetrahydroquinazoline-6-carboxamide;6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinazoline-6-carboxamide;(S)-2-(2-Chlorophenyl)-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;(R)-2-(2-Chlorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;(R)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;(S)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-1-isopropyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(R)-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;(S)-6-(3-fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;(R)-2-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxamide;(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;(S)-1-Cyclopropyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(R)-1-Cyclopropyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxamide;E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(2-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(3-(trifluoromethyl)benzyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(R)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(S)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(R)-2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-methoxypyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(S)-2-Cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;(S)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(o-tolyl)-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;E1-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;E2-(abs)-5-(3-Fluoro-2-methylphenyl)-2-(4-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;E1-(abs)-2-(1,5-Dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;E2-(abs)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide;(S)-6-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)-N-hydroxy-5,6-dihydro-4H-cyclopenta[d]thiazole-6-carboxamide;(R)-5-(3-Fluoro-2-methylphenyl)-3-(4-fluorophenyl)-N-hydroxy-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;E1-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide;E2-(abs)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-3-phenyl-5,6-dihydro-4H-cyclopenta[d]isothiazole-5-carboxamide;2-(3-Fluoro-2-methylphenyl)-N-hydroxy-2,3-dihydro-1H-indene-2-carboxamide;2-Cyclopropyl-7-(3-fluoro-2-methylphenyl)-N-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine-7-carboxamide;E1-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;E2-(abs)-6-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;andN-Hydroxy-6-phenyl-2-(2,2,2-trifluoroethyl)-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-6-carboxamide;E1-(abs)-N-Hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide;E2-(abs)-N-hydroxy-1-phenyl-2,3-dihydro-1H-indene-1-carboxamide;N-Hydroxy-2-phenyl-2,3-dihydro-1H-indene-2-carboxamide;(S)-1-(2-Chloro-4-fluorophenyl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-2-(4,6-Dimethylpyrimidin-2-yl)-5-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(S)-1-Benzyl-5-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-5-carboxamide;(R)-1-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;(R)-2-Benzyl-4-(3-fluoro-2-methylphenyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;(R)-4-(3-fluoro-2-methylphenyl)-2-(2-fluorobenzyl)-N-hydroxy-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-4-carboxamide;and(R)-5-(3-Fluoro-2-methylphenyl)-N-hydroxy-2-(5-fluoropyridin-2-yl)-5,6-dihydro-4H-cyclopenta[d]thiazole-5-carboxamide.50. A pharmaceutical composition comprising a compound according toclaim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 51. A process for preparing apharmaceutical composition comprising admixing a compound according toclaim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.